Topical naftifine compositions

Abstract

The present disclosure provides a topical spray composition comprising: (a) from about 0.05% to about 5% by weight of naftifine, or a pharmaceutically acceptable salt thereof, (b) a film former comprising an octyl acrylamide acrylate copolymer, and (c) an alcoholic solvent comprising at least one of an organic solvent, an organic solvent, and an organic solvent, a topical spray composition wherein the ratio of the alcoholic solvent to propellant in the composition is from about 1: 1 to about 3: 1 (w / w). The disclosure also provides a method of treating a dermatophyte skin infection or onychomycosis in a subject in need thereof, the method comprising topically administering to the subject a topical composition as described herein.

Description

Technical Field

[0001] The present disclosure provides a topical spray composition comprising: (a) about 0.05% to about 5% by weight of naftifine or a pharmaceutically acceptable salt thereof, (b) a film former comprising octylacrylamide acrylate copolymer, and (c) an alcohol solvent, and (d) a propellant, wherein the ratio of the alcohol solvent to the propellant in the composition is about 1:1 to about 3:1 (w / w). The present disclosure also provides a drug-device combination for dispensing the composition disclosed herein. Additionally, the present disclosure also provides a method for treating a dermatophyte skin infection or onychomycosis in a subject in need thereof, the method comprising topically administering to the subject a topical spray composition as described herein. Background Art

[0002] Dermatophyte skin infections are common in the human population. Tinea pedis (commonly referred to as "athlete's foot") is a fungal (e.g., dermatophyte) infection of the soles of the feet and the spaces between the toes. Symptoms include cracking, blistering, or peeling of areas of skin, causing itching, stinging, and burning. Tinea cruris is a dermatophyte infection that affects the genitals, pubic bones, perineum, and perianal skin of the body. Common in athletes and people who frequently sweat in hygroscopic areas, tinea cruris is also known as "jock itch." If the infection is severe or untreated, the infection may cause redness, flaking, shedding, or cracking of the skin in the groin area and produce a foul odor. While tinea pedis and tinea cruris are caused by a variety of fungi, the most common being Trichophyton rubrum, Trichophyton interdigitale, Tinea capitis, and Epidermophyton floccosum, tinea corporis (also known as "ringworm") is a dermatophyte infection characterized by the appearance of a red, itchy, annular rash or lesion on the skin of any part of the body except the scalp, groin, palms, and soles of the feet. If not effectively treated, dermatophyte infections may recur and may lead to other serious medical conditions. Additionally, individuals with at least one dermatophyte infection on their body may develop other dermatophyte infections elsewhere on the body. Onychomycosis is a fungal infection of the nails that causes discoloration, thickening, and separation from the nail bed.

[0003] Currently, various creams and ointments are commercially available for the treatment of dermatophyte infections such as tinea pedis and onychomycosis. Commercial formulations include the active ingredient Terbinafine and LamisilOnce, Naftifine and Luliconazole and various azoles, such as Clotrimazole. However, creams and ointments can be difficult to apply, are inconvenient, and may involve a messy application process. Summary of the invention

[0004] The present disclosure relates to a spray-type topical composition comprising: (a) about 0.05 wt % to about 5 wt % of naftifine or a pharmaceutically acceptable salt thereof, (b) a film former comprising octylacrylamide acrylate copolymer, (c) an alcohol solvent, and (d) a propellant, wherein the ratio of the alcohol solvent to the propellant in the composition is about 1:1 to about 3:1 (w / w).

[0005] In one embodiment, the present disclosure relates to a topical composition comprising: (a) about 0.05 wt % to about 5 wt % of naftifine or a pharmaceutically acceptable salt thereof, (b) a film former, (c) an alcohol solvent, and (d) a propellant, wherein the ratio of the alcohol solvent to the propellant in the composition is about 1:1 to about 3:1 (w / w).

[0006] In some embodiments, the naftifine or a pharmaceutically acceptable salt thereof is naftifine hydrochloride. In some embodiments, the composition comprises about 1% to about 3% of naftifine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 2% of naftifine or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the composition comprises about 2% w / w to about 10% w / w of octyl acrylamide acrylate copolymer. In some embodiments, the composition comprises about 2% w / w to about 4% w / w of octyl acrylamide acrylate copolymer. In some embodiments, the ratio of the film former to the alcohol solvent in the composition is about 1:15 to 1:30 (w / w). In some embodiments, the ratio of the film former to the alcohol solvent in the composition is about 1:18 to 1:22 (w / w).

[0008] In some embodiments, the composition comprises less than 4% of a hydrophilic polymer. In some embodiments, the composition comprises less than 0.5% of a hydrophilic polymer.

[0009] In some embodiments, the alcohol solvent is C 1-6 In some embodiments, the C 1-6 The alcohol is methanol, ethanol, propanol, n-propanol, isopropanol, n-butanol, tert-butanol, 2-butanol, isobutanol, pentanol, hexanol, cyclohexanol or a combination thereof.

[0010] In some embodiments, the alcohol solvent has a viscosity of about 1 cp to about 150 cp. In some embodiments, the composition comprises about 10 wt % to about 70 wt % of the alcohol solvent. In some embodiments, the composition comprises about 50 wt % to about 70 wt % of the alcohol solvent. In some embodiments, the composition comprises less than 70 wt % of the alcohol solvent.

[0011] In some embodiments, the viscosity of the composition is from about 0.1 cp to about 500 cp. In some embodiments, the viscosity of the composition is from about 1 cp to about 150 cp.

[0012] In some embodiments, the propellant is a hydrocarbon propellant, a fluorocarbon propellant, a hydrofluorocarbon propellant, or a combination thereof. In some embodiments, the propellant is propane, isobutane, n-butane, isopentane, n-pentane, or a combination thereof. In some embodiments, the propellant is a hydrofluorocarbon propellant. In some embodiments, the hydrofluorocarbon propellant is 1,1,1,2-tetrafluoroethane (Norflurane 134A; HFA-134a) or 1,1-difluoroethane (HFA-152a). In some embodiments, the composition comprises about 10% to about 50% by weight of the propellant. In some embodiments, the composition comprises about 25% to about 45% by weight of the propellant.

[0013] In some embodiments, the ratio of the alcohol solvent to the propellant is about 1.5:1 to about 2.5:1 (w / w). In some embodiments, the ratio of the alcohol solvent to the propellant is about 1:1 to 2:1 (w / w). In some embodiments, the ratio of the alcohol solvent to the propellant is about 2:1 to 3:1 (w / w). In some embodiments, the ratio of the film former to the propellant is about 1:7 to 1:15 (w / w). In some embodiments, the ratio of the film former to the propellant is about 1:8 to 1:12 (w / w).

[0014] In certain embodiments, the composition further comprises a penetration enhancer, a cosolvent, an emulsifier, a solubilizing agent or a combination thereof. In certain embodiments, the penetration enhancer is a mixture of diethylene glycol monoethyl ether, diethyl sebacate, diisopropyl adipate, dimethyl isosorbide, dimethyl sulfoxide, polyethylene glycol, oleic acid, lactic acid esters, oleyl alcohol, alkyl glycosides, sugar alkyl esters, dimethyl formamide, isopropyl myristate, Tween (Tween) 80, sodium lauryl sulfate, oleic acid and octyl dimethyl para-aminobenzoic acid or a combination thereof. In certain embodiments, the penetration enhancer is a combination of propylene glycol and diethylene glycol monoethyl ether. In certain embodiments, the composition comprises an penetration enhancer of about 0.1% to about 7% (w / w). In certain embodiments, the composition comprises an penetration enhancer of about 0.5% to about 2.5% (w / w).

[0015] In some embodiments, the present disclosure provides a spray-type topical composition comprising: (a) about 0.05 wt % to about 5 wt % of naftifine or a pharmaceutically acceptable salt thereof; (b) a film former comprising octylacrylamide acrylate copolymer; (c) about 50 wt % to about 75 wt % of an alcohol solvent; and (d) about 20 wt % to about 45 wt % of a propellant.

[0016] In some embodiments, the present disclosure provides a spray-type topical composition comprising: (a) about 0.05 wt % to about 5 wt % of naftifine or a pharmaceutically acceptable salt thereof, (b) about 1 wt % to about 5 wt % of a film former comprising octylacrylamide acrylate copolymer, (c) about 25 wt % to about 45 wt % of a propellant, (d) about 50 wt % to about 70 wt % of an alcohol solvent, and (e) about 1 wt % to about 3.5 wt % of a penetration enhancer.

[0017] In one embodiment, the present disclosure provides a spray-type topical composition comprising: (a) about 0.05 wt % to about 5 wt % of naftifine or a pharmaceutically acceptable salt thereof, (b) about 1 wt % to about 5 wt % of a film former, (c) about 25 wt % to about 45 wt % of a propellant, (d) about 50 wt % to about 70 wt % of an alcohol solvent, and (e) about 1 wt % to about 3.5 wt % of a penetration enhancer.

[0018] In some embodiments, the present disclosure provides a delivery device comprising a topical composition as described herein. In some embodiments, the delivery device is a sealed and pressurized device. In some embodiments, the pressure in the sealed and pressurized device is from about 28 psi to about 145 psi at 25° C. In some embodiments, the delivery device comprises a means for providing an aerosol spray of the topical composition. In some embodiments, the delivery device comprises a means for providing a non-aerosol spray of the topical composition.

[0019] In some embodiments, the present disclosure provides an article of manufacture for treating a dermatophyte skin infection or onychomycosis in a subject in need thereof, the article of manufacture comprising (a) a sealed, pressurized container comprising (i) the topical composition as described herein, and (ii) means for providing an aerosol spray of the topical composition, and (b) instructions for using the topical composition for treating the dermatophyte skin infection or onychomycosis.

[0020] In some embodiments, the present disclosure provides a method of treating a dermatophyte skin infection or onychomycosis in a subject in need thereof, the method comprising topically administering to the subject the topical composition as described herein. In some embodiments, the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris. In some embodiments, the administering comprises applying the topical composition to the subject as an aerosol spray.

[0021] In some embodiments, the composition is applied no more than once within a three-day period. In some embodiments, the composition is applied no more than once within a one-week period. In some embodiments, the composition is applied no more than once within a two-week period. In some embodiments, the topical composition is applied to the subject no more than twice to relieve the dermatophyte skin condition or onychomycosis. In some embodiments, the topical composition is applied to the subject once to relieve the dermatophyte skin condition or onychomycosis. In some embodiments, the method comprises applying the topical composition for the first time and applying the topical composition for the second time. In some embodiments, the second composition is 5 to 10 days after the first application. In some embodiments, the second composition is about 7 days after the first application.

[0022] In some embodiments, effectiveness in treating the dermatophyte skin condition is determined by: (a) comparing clinical signs and symptoms associated with tinea pedis in (i) subjects treated with the topical composition to (ii) subjects treated with a placebo; and / or (b) comparing mycological cure rates (i.e., potassium hydroxide stain and fungal culture results) in (i) subjects treated with the topical composition to (ii) subjects treated with a placebo. In some embodiments, the average systemic level of naftifine after a single application of the topical spray composition is about 100 pg / mL after 4 weeks.

[0023] In some embodiments, the present disclosure provides a method of treating a dermatophyte skin infection or onychomycosis in a patient, the method comprising administering to the subject two doses of a topical composition comprising naftifine, wherein the topical composition is a monophasic solution and the naftifine is present at at least 80% saturation under conditions of use, wherein the second dose is administered about 1 week after the first dose. In some embodiments, the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris.

[0024] In some embodiments, the present disclosure provides a method of treating a dermatophyte skin infection or onychomycosis in a patient, the method comprising administering to the subject a dose of a topical composition comprising naftifine, wherein the topical composition is a monophasic solution and the naftifine is present at at least 80% saturation under conditions of use. In some embodiments, the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris.

[0025] In some embodiments, the present disclosure provides a method for maintaining a therapeutic level of naftifine in the stratum corneum of a subject above the minimum inhibitory concentration (MIC). The MIC is the lowest concentration of an antimicrobial agent required to inhibit visible in vitro growth of a challenging microorganism.

[0026] In some embodiments, the present disclosure provides a method for maintaining therapeutic levels of naftifine in the stratum corneum of a subject above the MIC for 1 week, 2 weeks, 4 weeks, or 8 weeks, the method comprising administering to the subject two doses of a topical composition comprising naftifine, wherein the composition is a monophasic solution and the drug is present at at least 80% saturation under conditions of use, wherein the second dose is administered about 1 week after the first dose. In some embodiments, four weeks after the first dose and three weeks after the second dose, the amount of naftifine in the stratum corneum of the subject is, on average, half the amount extracted at the second dose.

[0027] In some embodiments, the present disclosure provides a method for maintaining therapeutic levels of naftifine in the stratum corneum of a subject above the MIC for 1 week, 2 weeks, 4 weeks, or 8 weeks, the method comprising administering to the subject a single dose of a topical composition comprising naftifine, wherein the composition is a single-phase solution and the drug is present at at least 80% of saturation under conditions of use.

[0028] In some embodiments, the present disclosure provides a method of treating a dermatophyte skin infection or onychomycosis in a subject in need thereof, the method comprising administering a spray-on topical composition comprising 2% naftifine or a pharmaceutically acceptable salt thereof, wherein the topical composition is administered to the patient in one dose or two doses, wherein if two doses are used, the second dose is administered about 1 week after the first dose, wherein the administering of the topical composition to the subject achieves at least 10%, 20%, 30%, 40% or 50% success rate of efficacy endpoints. In some embodiments, the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris. In some embodiments, efficacy is measured using mycological cure (KOH and fungal culture), efficacy (defined as negative KOH staining, negative fungal culture, and absence or mild erythema, desquamation, and pruritus), and clinical cure (defined as absence of erythema, desquamation, and pruritus). In some embodiments, the primary efficacy endpoint is to achieve complete clearance at day 42 (6 weeks), which is defined as negative KOH, negative fungal culture, and absence of individual signs and symptoms (i.e., erythema, desquamation, and pruritus). In some embodiments, the percentage of subjects administered the topical composition achieves the primary efficacy endpoint at twice the percentage of subjects administered a placebo or received no treatment.

[0029] In some embodiments, the present disclosure provides a method of treating a dermatophyte skin infection or onychomycosis in a subject, the method comprising administering a topical composition comprising naftifine, wherein the composition is a monophasic solution and the drug is present at at least 80% saturation under conditions of use, wherein the administering of the topical composition to the subject achieves complete clearance of symptoms and improvement in an associated parameter selected from the following: (a) a decrease in severity of erythema at day 42, with a score of 0 relative to baseline; (b) a decrease in severity of desquamation at day 42, with a score of 0 relative to baseline; (c) a decrease in severity of pruritus at day 42, with a score of 0 relative to baseline; or a combination thereof. In some embodiments, the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris.

[0030] In some embodiments, the present disclosure provides a method of treating a dermatophyte skin infection in a subject, the method comprising administering a topical spray composition comprising naftifine, wherein the composition is a monophasic solution and the drug is present at at least 80% saturation under conditions of use, wherein said administering of the topical composition to the subject results in a treatment efficacy of at least 20%, wherein the efficacy is negative KOH stain, negative fungal culture, and absent or mild erythema, scaling, and pruritus six weeks after said treatment.

[0031] In some embodiments, the method comprises administering a single dose of the topical spray composition. In some embodiments, the method comprises administering two doses of the topical spray composition. In some embodiments, administering the topical composition to the subject produces at least 40% therapeutic efficacy. In some embodiments, administering the topical composition to the subject produces at least 70% therapeutic efficacy.

[0032] In some embodiments, the present disclosure provides a drug-device combination for dispensing a composition, the drug-device combination comprising a container, the container comprising a composition, the composition comprising naftifine or a pharmaceutically acceptable salt thereof; a film former, the film former comprising octylacrylamide acrylate copolymer; an alcohol solvent; and a propellant, wherein the drug-device combination is suitable for providing a spray comprising the composition, wherein the D 90 The droplet size is larger than 1 μm.

[0033] In some embodiments, when sprayed from the device, the composition of the drug-device combination has a D 90 The droplet size is about 140 μm to about 170 μm. In some embodiments, when sprayed from the device, the composition of the drug-device combination has a D 90 The droplet size is about 150 μm to about 165 μm. In some embodiments, when sprayed from the device, the average D 90 The droplet size was about 155 μm to 163 μm.

[0034] In some embodiments, the composition of the drug-device combination comprises naftifine or a pharmaceutically acceptable salt thereof is naftifine hydrochloride. In some embodiments, the composition of the drug-device combination comprises about 1% to about 3% naftifine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition of the drug-device combination comprises about 2% naftifine or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the composition of the drug-device combination comprises about 2% w / w In some embodiments, the composition of the drug-device combination comprises about 2% w / w to about 4% w / w of octylacrylamide acrylate copolymer. In some embodiments, the composition of the drug-device combination comprises a composition wherein the ratio of the film former to the alcohol solvent in the composition is about 1:15 to 1:30 (w / w). In some embodiments, the composition of the drug-device combination comprises a composition wherein the ratio of the film former to the alcohol solvent in the composition is about 1:18 to 1:22 (w / w).

[0036] In some embodiments, the composition of the drug-device combination comprises less than 4% of a hydrophilic polymer. In some embodiments, the composition of the drug-device combination comprises a composition comprising less than 0.5% of a hydrophilic polymer.

[0037] In some embodiments, the alcohol solvent of the composition of the drug-device combination is a C1-C6 alcohol. In some embodiments, the C1-C6 alcohol of the composition of the drug-device combination is methanol, ethanol, propanol, n-propanol, isopropanol, n-butanol, tert-butanol, 2-butanol, isobutanol, pentanol, hexanol, cyclohexanol, or a combination thereof. In some embodiments, the C1-C6 alcohol of the composition of the drug-device combination is ethanol.

[0038] In some embodiments, the alcohol solvent of the composition of the drug-device combination has a viscosity of about 1 cp to about 150 cp. In some embodiments, the composition of the drug-device combination comprises about 10 wt % to about 70 wt % of the alcohol solvent. In some embodiments, the composition of the drug-device combination comprises about 50 wt % to about 70 wt % of the alcohol solvent.

[0039] In some embodiments, the drug-device combination comprises a composition, wherein the viscosity of the composition is about 0.1 cp to about 500 cp. In some embodiments, the drug-device combination comprises a composition, wherein the viscosity of the composition is about 1 cp to about 150 cp.

[0040] In some embodiments, the propellant of the composition of the drug-device combination is a hydrocarbon propellant, a fluorocarbon propellant, a hydrofluorocarbon propellant, or a combination thereof. In some embodiments, the propellant of the composition of the drug-device combination is propane, isobutane, n-butane, isopentane, n-pentane, or a combination thereof. In some embodiments, the propellant of the composition of the drug-device combination is a hydrofluorocarbon propellant. In some embodiments, the hydrofluorocarbon propellant of the composition of the drug-device combination is 1,1,1,2-tetrafluoroethane (Norflurane 134A; HFA-134a) or 1,1-difluoroethane (HFA-152a).

[0041] In some embodiments, the composition of the drug-device combination comprises about 10 wt % to about 50 wt % propellant. In some embodiments, the composition of the drug-device combination comprises about 25 wt % to about 45 wt % propellant.

[0042] In some embodiments, the drug-device combination comprises a composition wherein the ratio of the alcohol solvent to the propellant is about 1.5:1 to about 2.5:1 (w / w). In some embodiments, the drug-device combination comprises a composition wherein the ratio of the alcohol solvent to the propellant is about 1:1 to 2:1 (w / w). In some embodiments, the drug-device combination comprises a composition wherein the ratio of the alcohol solvent to the propellant is about 2:1 to 3:1 (w / w). In some embodiments, the drug-device combination comprises a composition wherein the ratio of the film former to the propellant is about 1:7 to 1:15 (w / w). In some embodiments, the drug-device combination comprises a composition wherein the ratio of the film former to the propellant is about 1:8 to 1:12 (w / w). In some embodiments, the composition of the drug-device combination further comprises a penetration enhancer, a solubilizer, an emulsifier, a solubilizer, or a combination thereof.

[0043] In some embodiments, the penetration enhancer of the composition of the drug-device combination is a mixture of diethylene glycol monoethyl ether, diethyl sebacate, diisopropyl adipate, dimethyl isosorbide, dimethyl sulfoxide, polyethylene glycol, oleic acid, lactic acid esters, oleyl alcohol, alkyl glycosides, sugar alkyl esters, dimethylformamide, isopropyl myristate, Tween 80, sodium lauryl sulfate, oleic acid and octyl dimethyl para-aminobenzoic acid, or a combination thereof.

[0044] In some embodiments, the pressure inside the drug-device combination is from about 28 psi to about 145 psi at 25°C.

[0045] In some embodiments, the present disclosure provides a method of treating a dermatophyte skin infection or onychomycosis in a subject in need thereof, the method comprising applying an aerosol spray to the skin using the drug-device combination disclosed herein. In some embodiments, the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris. In some embodiments, the composition is applied no more than once over a three-day period. In some embodiments, the composition is applied no more than once over a one-week period. In some embodiments, the composition is applied no more than once over a two-week period. In some embodiments, the composition is applied to the subject no more than twice to relieve the dermatophyte skin condition or onychomycosis. In some embodiments, the topical composition is applied once. In some embodiments, the composition is applied in one application.

[0046] In some embodiments, the composition dries in less than three minutes after being applied to the skin. In some embodiments, the composition dries in less than two minutes after being applied to the skin. In some embodiments, the composition dries in less than one minute after being applied to the skin.

[0047] In some embodiments, the method comprises applying the topical composition for the first time and applying the composition for the second time. In some embodiments, the second application is 5 to 10 days after the first application. In some embodiments, the second application is about 7 days after the first application. DETAILED DESCRIPTION

[0048] The present disclosure relates to compositions and methods suitable for treating dermatophyte skin infections (e.g., tinea pedis, tinea pedis between the toes, tinea cruris and tinea corporis or onychomycosis). In certain embodiments, the present disclosure provides a topical composition comprising naftifine, such as a topical aerosol spray. Naftifine cream has previously been used to treat dermatophyte infections, such as tinea pedis, tinea cruris and tinea corporis. However, the present disclosure provides a novel composition, which is a fast-acting, timely and effective treatment for dermatophyte infections and onychomycosis, with limited / reduced side effects. The topical composition of the present invention is also non-greasy and dries quickly. The present disclosure also provides a composition for effectively treating dermatophyte infections (such as tinea pedis, tinea pedis between the toes, tinea cruris and tinea corporis), which is accompanied by very little blood absorption and therefore has a low systemic effect. The topical composition provided herein reduces erythema, desquamation and itching of the skin. Additionally, the present disclosure provides compositions for treating dermatophyte infections (such as tinea pedis, interdigital tinea pedis, tinea cruris, tinea corporis, and tinea capitis), which are effective when applied in reduced dosage amounts (e.g., when applied to a subject in need once or twice). In some embodiments, the spray-on compositions described herein can be sprayed directly on the skin surface and do not need to be spread over the skin by contacting with fingers or with a separate applicator, thereby avoiding contact with uninfected body parts to areas affected by dermatophytes. In some embodiments, direct application to the skin by spraying provides increased convenience and reduces the delivery of naftifine to hands / fingers or other body parts that do not require the naftifine. In some embodiments, the spray-on compositions described herein can be applied quickly. In some embodiments, the spray-on compositions described herein can be effectively applied to less accessible areas, such as interdigital spaces. In some embodiments, the spray-on compositions described herein can be quickly applied to large areas of skin.

[0049] Although terbinafine is more soluble in alcohol than naftifine, surprisingly, the topical naftifine compositions of the present invention completely dissolve in the formulation and, after a single application, have skin penetration and skin retention rates that match the clinical antifungal efficacy obtained with the terbinafine Once product.

[0050] Unless otherwise defined herein, scientific terms and technical terms used in this disclosure should have the meanings commonly understood by those of ordinary skill in the art. In addition, unless the context otherwise requires, singular terms should include plural terms, and plural terms should include the singular. As used herein, "a / an" may mean one or more. As used herein, when used in conjunction with the word "comprising", the word "a" or "a kind of" may mean one or more than one. As used herein, "another" or "a further" may mean at least a second or more.

[0051] Throughout this application, the term "about" is used to indicate that a value includes variations in error inherent to the method / device used to determine the value or variations that exist between study subjects. Typically, the term "about" is intended to encompass approximately or less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% variability, depending on the circumstances.

[0052] The use of the term "or" in the claims is intended to mean "and / or" unless explicitly indicated to refer to only alternatives or the alternatives are mutually exclusive, although the present disclosure supports a definition referring to only alternatives and "and / or."

[0053] As used herein, the terms "comprising" (and any variations or forms of comprising, such as "comprise" and "comprises"), "having" (and any variations or forms of having, such as "have" and "has"), "including" (and any variations or forms of including, such as "includes" and "include"), or "containing" (and any variations or forms of containing, such as "contains" and "contain") are inclusive or open-ended, and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any protein, composition, polynucleotide, vector, cell, method, and / or kit of the present disclosure. In addition, the compositions, polynucleotides, vectors, cells, and / or kits of the present disclosure can be used to implement the methods and proteins of the present disclosure.

[0054] The use of the term "for example" and its corresponding abbreviation "eg" (whether italicized or not) means that the specific term referenced is a representative example and embodiment of the present disclosure, which is not intended to be limited to the specific example referenced or referenced unless otherwise expressly stated.

[0055] As used herein, "between" is a range that includes the endpoints of the range. For example, the numbers between x and y explicitly include the numbers x and y and any numbers falling within x and y.

[0056] The present disclosure provides a sprayable topical composition, such as a topical spray composition, comprising naftifine. In some embodiments, the present disclosure provides a topical composition comprising: (a) about 0.05% to about 5% by weight of naftifine or a pharmaceutically acceptable salt thereof, (b) a film former comprising octylacrylamide acrylate copolymer, and (c) an alcohol solvent, wherein the ratio of the alcohol solvent to the propellant in the composition is about 1:1 to about 3:1 (w / w).

[0057] In one embodiment, the film former can be one or more of the following: polyvinyl pyrrolidone, polyvinyl alcohol, acrylic acid polymer, acrylic acid copolymer, methacrylate polymer, octylacrylamide acrylate copolymer, methacrylate copolymer, poly (vinyl acetate), cellulose-based polymer, cellulose-based copolymer, collodion (nitrocellulose), pullulan (Pullulan, polysaccharide polymer), alginate.

[0058] Naftifine can be represented by Formula I.

[0059]

[0060] As used herein, the term naftifine includes compounds of Formula I, as well as salts, solvates, and stereoisomers thereof. For example, in some embodiments, naftifine includes naftifine hydrochloride, as well as other pharmaceutically acceptable salts.

[0061] The concentration of naftifine can vary in the composition. In certain embodiments, the concentration of naftifine is less than 5% by weight of the composition. In certain embodiments, the concentration of naftifine is less than 4.5% by weight, less than 4.0% by weight, less than 3.5% by weight or less than 3.0% by weight of the composition. In certain embodiments, the composition comprises about 0.05% by weight to about 5% by weight of naftifine. In certain embodiments, the composition comprises about 0.05% by weight to about 4% by weight, about 0.1% by weight to about 3.5% by weight, about 0.1% by weight to about 3.0% by weight, about 0.2% by weight to about 3.0% by weight, about 0.5% by weight to about 2.5% by weight, about 1.0% by weight to about 3.0% by weight, about 1.0% by weight to about 2.5% by weight, about 1.5% by weight to about 2.5% by weight, about 1.8% by weight to about 2.2% by weight or about 2.0% by weight of naftifine.

[0062] The present disclosure provides a topical composition for application. In some embodiments, the present disclosure provides a topical aerosol spray composition for application. In some embodiments, the term topical aerosol spray composition is a pressurized composition, such as a composition in a closed container under pressure, so that an aerosol can be formed when released from the container. In some embodiments, the topical composition may include a pressurized or unpressurized composition. For example, the term "topical composition" may include (i) a liquid composition inside a pressurized container, which becomes an aerosol spray when discharged from the container, and (2) an aerosol spray discharged from the container. Additionally, in some embodiments, the term "topical composition" may include a liquid composition on a surface (e.g., a skin surface), and when the aerosol spray contacts the surface, the liquid composition is formed. In some embodiments, application by aerosol spray provides a more consistent composition application to the subject being treated. In some embodiments, application by aerosol spray provides a more thorough composition application to the subject, such as covering a larger area. In some embodiments, application by aerosol spray provides a more convenient application method. In some embodiments, application by aerosol spray reduces the need for other applicators, such as wipes, gauze, fabric, etc. In some embodiments, application by aerosol spray reduces exposure of the hands or other unintended body parts to the presence of naftifine that can occur through application as a cream, gel, or liquid. In some embodiments, application by aerosol spray provides a more convenient mode of application because it allows for rapid drying of the composition after application.

[0063] In some embodiments, the treatment of dermatophyte skin infection or onychomycosis comprises applying the topical composition to the subject with an aerosol spray. In some embodiments, the topical composition is a single-phase solution. In some embodiments, the topical composition is a saturated single-phase solution as outlined in US8,349,297, which is incorporated herein by reference in its entirety. As used herein, the term "single-phase" indicates that the composition does not contain undissolved components (such as naftifine or any other excipients), and there is only one liquid phase, and is not a colloid or microglial composition. Therefore, in some embodiments, the topical composition has only one phase, and the phase is liquid.

[0064] In some embodiments, the term "saturated" may include substantially saturated, wherein there is at least 80%, at least 90%, or at least 95% of the amount of naftifine required to achieve saturation. In some embodiments, the composition is as close to saturation as possible while maintaining a single phase at the use temperature. The term "saturated" may also include a supersaturated solution under certain conditions.

[0065] In some embodiments, the amount of naftifine is as close to full saturation as possible. In some embodiments, the addition of an anti-nucleating agent may be advantageous because the saturation may drop slightly, as low as 80%, which may be considered a saturation amount for purposes of the present invention.

[0066] The present disclosure provides a naftifine composition comprising a film former. The present disclosure shows that in a topical composition (e.g., a topical spray composition), a film former comprising an octyl acrylamide acrylate copolymer provides a more lasting effect for the treated area while minimizing the systemic exposure of naftifine. In some embodiments, the lasting effect of the composition of the present invention allows the total number of applications of the naftifine composition to be reduced. In some embodiments, the lasting effect of the composition of the present invention allows the frequency of application of the naftifine composition to be reduced.

[0067] In some embodiments, the composition comprises a film former comprising an octylacrylamide acrylate copolymer. The term octylacrylamide acrylate copolymer refers to an octylacrylamide polymer having one or more monomers of a simple ester of acrylic acid, methacrylic acid, or a simple ester thereof. Various octylacrylamide acrylate copolymers are known in the art and may include an octylacrylamide / acrylate / butylaminoethyl methacrylate copolymer. In some embodiments, the octylacrylamide acrylate copolymer is Polymer (Nouryon), a hydrophobic, high molecular weight carboxylated acrylic acid copolymer. Also known as acrylate-tert-octylacrylamide. In some embodiments, the octylacrylamide acrylate copolymer is Dermacryl LT (carboxylated acrylic acid copolymer of acrylates and octylacrylamide). In some embodiments, the octylacrylamide acrylate copolymer is Dermacryl E (styrene\acrylate copolymer). In some embodiments, the topical composition may have more than one film former. In some embodiments, the octylacrylamide acrylate copolymer comprises greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, or greater than 95% of the film former in the topical composition. In some embodiments, the topical composition comprises octylacrylamide acrylate copolymer as the sole film former.

[0068] Various concentrations of film formers are present in the topical composition. In some embodiments, the topical composition comprises less than 10 wt%, less than 8 wt%, less than 6 wt%, less than 5 wt%, or less than 4 wt% of the film former. In some embodiments, the topical composition comprises greater than 0.5 wt%, greater than 1.0 wt%, greater than 1.5 wt%, greater than 2.0 wt%, or greater than 2.5 wt% of the film former. In some embodiments, the topical composition comprises about 1 wt% to about 10 wt% of octyl acrylamide acrylate copolymer. In some embodiments, the topical composition comprises about 1.5 wt% to about 8.0 wt%, about 1.5 wt% to about 6.0 wt%, about 2.0 wt% to about 4.0 wt%, or about 2.5 wt% to about 3.5 wt% of octyl acrylamide acrylate copolymer.

[0069] The present disclosure provides various ratios of film formers to alcohol solvents in the topical compositions. In some embodiments, these ratios provide stable compositions that are suitable for dissolving naftifine while being suitable for topical application (e.g., by spraying, e.g., an aerosol spray or a mist spray). In some embodiments, the ratio of the film former to the alcohol solvent in the composition is about 1:10 to about 1:40 (w / w). In some embodiments, the ratio of the film former to the alcohol solvent in the composition is about 1:15 to 1:30, about 1:16 to about 1:25, or about 1:18 to 1:22 (w / w). In some embodiments, the ratio of the film former to the alcohol solvent in the composition is about 1:20.

[0070] The applicants of the present disclosure have found that, in some embodiments, the hydrophilic polymer previously used in the dermal composition is not needed in the composition described herein. In some embodiments, the present disclosure provides a topical composition with a low concentration of hydrophilic polymer (e.g., less than 5% of the hydrophilic polymer). In some embodiments, the present disclosure provides a topical composition without a hydrophilic polymer. In some embodiments, the composition comprises less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight or less than 0.5% by weight of the hydrophilic polymer. In some embodiments, the hydrophilic polymer reduced or excluded from the topical composition is polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymer, hydroxyalkyl cellulose and / or alkyl cellulose. In some embodiments, a topical composition with reduced hydrophilic polymer (or without hydrophilic polymer) provides an increased physical stability of the topical composition. In some embodiments, a topical composition with reduced hydrophilic polymer (or without hydrophilic polymer) provides an increased chemical stability of the topical composition. In some embodiments, a topical composition with reduced hydrophilic polymer (or without hydrophilic polymer) provides a viscosity suitable for spraying (e.g., aerosol spray). In some embodiments, the topical composition with reduced hydrophilic polymer (or without hydrophilic polymer) provides a spray that is more evenly dispersed and does not clog the dispersion device (e.g., aerosol device). In some embodiments, the topical composition with reduced hydrophilic polymer (or without hydrophilic polymer) provides a faster drying time relative to the composition comprising hydrophilic polymer. In some embodiments, the topical composition with reduced hydrophilic polymer (or without hydrophilic polymer) results in less residue on the skin of the treated subject. In some embodiments, the topical composition with reduced hydrophilic polymer (or without hydrophilic polymer) provides a composition that adheres to the skin for a longer period of time than the composition comprising hydrophilic polymer. In some embodiments, the topical composition with reduced hydrophilic polymer (or without hydrophilic polymer) provides a more economical composition, making the manufacture of the topical composition simpler, faster, cheaper and / or requiring less equipment, thereby simplifying manufacture relative to the composition requiring hydrophilic polymer.

[0071] Various solvents can be used in the present invention. In some embodiments, the solvent (e.g., an organic solvent) is suitable for dissolving pharmaceutically acceptable naftifine. In some embodiments, the solvent is an alcohol solvent. In some embodiments, the alcohol solvent is C 1-6 In some embodiments, the C 1-6The alcohol is methanol, ethanol, propanol, n-propanol, isopropanol, n-butanol, tert-butanol, 2-butanol, isobutanol, amyl alcohol, hexanol, cyclohexanol or a combination thereof. In certain embodiments, the alcohol solvent has a viscosity suitable for application by aerosol spray or mist. In certain embodiments, the viscosity of the alcohol solvent is from about 1cp to about 150cp.

[0072] In some embodiments, the composition comprises an alcohol solvent of about 10% by weight to about 80% by weight. In some embodiments, the composition comprises an alcohol solvent of about 20% by weight to about 80% by weight, about 30% by weight to about 80% by weight, about 40% by weight to about 80% by weight or about 50% by weight to about 80% by weight. In some embodiments, the composition comprises an alcohol solvent of about 52% by weight to about 68% by weight, about 54% by weight to about 66% by weight, about 56% by weight to about 64% by weight or about 58% by weight to about 62% by weight. In some embodiments, the composition comprises an alcohol solvent of about 60% by weight. In some embodiments, the composition comprises an alcohol solvent of less than 80% by weight, less than 70% by weight, less than 65% by weight, less than 62% by weight or less than 61% by weight. In some embodiments, the composition comprises an alcohol solvent of about 70% by weight to about 85% by weight, an alcohol solvent of about 72% by weight to about 82% by weight or an alcohol solvent of about 74% by weight to about 80% by weight. In some embodiments, the composition comprises about 75 wt%, about 76 wt%, about 77 wt%, about 78 wt%, about 79 wt%, about 80 wt%, about 81 wt%, about 82 wt%, or about 83 wt% of an alcohol solvent. In some embodiments, reduced alcohol solvent concentrations can result in reduced adverse effects, such as inflammation or irritation.

[0073] In some embodiments, the composition comprises from about 10 wt % to about 70 wt % of C 1-6 In some embodiments, the composition comprises about 20% to about 70% by weight, about 30% to about 70% by weight, about 40% to about 70% by weight, or about 50% to about 70% by weight of C 1-6 In some embodiments, the composition comprises about 52% to about 68% by weight, about 54% to about 66% by weight, about 56% to about 64% by weight, or about 58% to about 62% by weight of C 1-6 In some embodiments, the composition comprises about 70% to about 85% by weight of C 1-6 alcohol solvent, about 72 wt % to about 82 wt % of C 1-6 alcohol solvent or about 74 wt % to about 80 wt % of C 1-6In some embodiments, the composition comprises about 75 wt%, about 76 wt%, about 77 wt%, about 78 wt%, about 79 wt%, about 80 wt%, about 81 wt%, about 82 wt%, or about 83 wt% of C 1-6 In some embodiments, the composition comprises about 60% by weight of C 1-6 Alcohol solvent.

[0074] In some embodiments, the present disclosure provides a spray-type topical composition comprising: (a) about 0.05% to about 5% by weight of naftifine or a pharmaceutically acceptable salt thereof; (b) a film former comprising an octylacrylamide acrylate copolymer; (c) about 50% to about 80% by weight of an alcohol solvent; and (d) about 15% to about 45% by weight of a propellant. In some embodiments, the present disclosure provides a spray-type topical composition comprising: (a) about 0.05% to about 5% by weight of naftifine or a pharmaceutically acceptable salt thereof, (b) about 1% to about 5% by weight of a film former comprising an octylacrylamide acrylate copolymer, (c) about 15% to about 45% by weight of a propellant, (d) about 50% to about 80% by weight of an alcohol solvent, and (e) about 1% to about 3.5% by weight of a penetration enhancer. In some embodiments, the present disclosure provides a spray-type topical composition comprising: (a) about 0.05 wt % to about 5 wt % of naftifine or a pharmaceutically acceptable salt thereof, (b) a film former comprising octylacrylamide acrylate copolymer, (c) an alcohol solvent, and (d) a propellant, wherein the film formation time is less than about 30 seconds.

[0075] In some embodiments, the ratio of alcohol solvent to propellant is from about 1:1 to about 3:1, about 1.1 ∶ 1 to about 2.9:1, about 1.2:1 to about 2.8:1, about 1.3:1 to about 2.7 ∶ 1. about 1.4:1 to about 2.6:1, about 1.5:1 to about 2.5:1, about 1.6:1 to about 2.4:1, about 1.7:1 to about 2.3:1 or about 1.8:1 to about 2.2:1.

[0076] In some embodiments, the topical composition has a viscosity suitable for application by aerosol spray and / or mist. For example, in some embodiments, the viscosity of the topical composition is less than 1000cp, less than 700cp, less than 500cp or less than 300cp. In some embodiments, the viscosity of the local formation is from about 1cp to about 500cp, from about 5cp to about 300cp or from about 50cp to about 250cp. In some embodiments, the viscosity of the topical composition is from about 1cp to about 150cp. As used throughout this disclosure, viscosity is measured under standard conditions, such as a pressure of 1atm and a temperature of 25°C.

[0077] In some embodiments, the topical composition generates an aerosol when discharged from a pressurized container using a standard single-fluid aerosol nozzle (e.g., a flat orifice nozzle or a shaped orifice nozzle (e.g., a "V" notch nozzle). In some embodiments, the composition is discharged at a pressure drop of about 20 bar to about 30 bar (e.g., about 25 bar (2,500 kPa; 360 psi)) at room temperature. In some embodiments, the droplet size of the aerosol is about 10 μm to about 100 μm. In some embodiments, at least 99% of the droplets have a diameter of 100 μm and above. In some embodiments, at least 99% of the droplets have a diameter of 100 μm and below.

[0078] In some embodiments, the topical composition further comprises a penetration enhancer, a solubilizing agent, an emulsifier, a propellant, a solubilizing agent, or a combination thereof. In some embodiments, the topical composition further comprises a propellant. In some embodiments, the propellant is a hydrocarbon propellant, a fluorocarbon propellant, a hydrofluorocarbon propellant, or a combination thereof. In some embodiments, the propellant is propane, isobutane, n-butane, isopentane, n-pentane, or a combination thereof. In some embodiments, the propellant is a hydrofluorocarbon propellant. In some embodiments, the hydrofluorocarbon propellant is 1,1,1,2-tetrafluoroethane ( 134A, HFA-134a) or 1,1-difluoroethane (HFA-152a, 152a).

[0079] In some embodiments, the propellant provides a high saturation level of naftifine. In some embodiments, the propellant is a highly volatile liquid with a low boiling point, such as a CFC or HFA, so that it can force the composition out of the dispenser. In some embodiments, the propellant provides that evaporation is almost instantaneous, and boiling has the effect of causing a large amount of solvent to evaporate during transfer from the dispenser to the application site. Therefore, in some embodiments, the solvent is preferably a volatile solvent, and is preferably more volatile than water, and will typically be organic. In some embodiments, during application, decompression of the propellant causes the solvent to be destroyed and lost through evaporation. This loss can be as high as 50% and even higher.

[0080] In some embodiments, the topical composition comprises various concentrations of propellant. In some embodiments, the concentration of the propellant is suitable for providing an aerosol naftifine spray. In some embodiments, the concentration of the propellant is suitable for providing a naftifine mist spray. In some embodiments, the composition comprises about 10% to about 50% by weight of the propellant. In some embodiments, the composition comprises about 25% to about 45% by weight of the propellant.

[0081] The present disclosure provides various ratios of film former to propellant that can be used in the topical composition. In some embodiments, the ratio of film former to propellant is about 1:7 to 1:15, about 1:7 to about 1:14, or about 1:8 to about 1:13 (w / w). In some embodiments, the ratio of film former to propellant is about 1:8 to 1:12 (w / w).

[0082] The present disclosure provides various ratios of alcohol solvent to propellant for use in the topical compositions described herein. In some embodiments, the ratio of the alcohol solvent to the propellant is from about 1:1 to about 3:1, from about 1.5:1 to about 1:1, or from about 2:1 to about 1:1 (w / w). In some embodiments, the ratio of the alcohol solvent to the propellant is from about 1:2 to about 1:3. In some embodiments, the ratio of the alcohol solvent to the propellant is about 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, or 2.9:1, 3:1, or any range containing any two of these ratios. In some embodiments, the disclosed ratios of alcohol solvent to propellant provide physically stable compositions, e.g., no particles are formed, the composition is homogeneous, naftifine is soluble, etc. In some embodiments, the disclosed ratios of alcohol solvent to propellant provide chemically stable compositions, e.g., naftifine does not degrade for an extended period of time (e.g., 3 months, 6 months, 9 months, 1 year, 18 months, and / or 2 years) under RT conditions or accelerated conditions.

[0083] In certain embodiments, the topical composition may include a penetration enhancer. The term "penetration enhancer" refers to any compound or composition that interacts with the outermost and rate-limiting layer stratum corneum (SC) of the skin and increases its permeability. A penetration enhancer may include a material that temporarily promotes naftifine to be absorbed into the skin by transiently enhancing skin permeability. A penetration enhancer may be used to transfer the delivery of naftifine while minimizing the systemic delivery of naftifine in the blood. As used herein, the penetration enhancer may include a mixture or a combination of diethylene glycol monoethyl ether, diethyl sebacate, diisopropyl adipate, dimethyl isosorbide, dimethyl sulfoxide, polyethylene glycol, oleic acid, lactic acid esters, oleyl alcohol, alkyl glycosides, sugar alkyl esters, dimethyl formamide, isopropyl myristate, Tween 80, sodium lauryl sulfate, oleic acid and octyl dimethyl para-aminobenzoic acid. In certain embodiments, there are one, two, three or more than three penetration enhancers in the topical composition. In certain embodiments, there are two penetration enhancers in the composition. In some embodiments, the penetration enhancer is propylene glycol and diethylene glycol monoethyl ether. combination.

[0084] Various concentrations of penetration enhancers may be present in the topical composition. The penetration enhancer may be adjusted to promote penetration of naftifine while minimizing systemic absorption. In some embodiments, the topical composition comprises from about 0.1 wt % to about 7 wt %, from about 0.2 wt % to about 5 wt %, from about 0.5 wt % to about 3 wt %, or from about 0.75 wt % to about 3 wt % of the penetration enhancer. In some embodiments, the composition comprises from about 0.5 wt % to about 2.5 wt % of the penetration enhancer.

[0085] In some embodiments, the topical composition comprises two penetration enhancers, wherein each penetration enhancer is about 0.1% to about 4% by weight, about 0.2% to about 3% by weight, about 0.5% to about 2% by weight, or about 0.5% to about 1.5% by weight of the topical composition. In some embodiments, the topical composition comprises one or both of propylene glycol and diethylene glycol monoethyl ether, wherein propylene glycol is about 0.1% to about 4% by weight, about 0.2% to about 3% by weight, about 0.5% to about 2% by weight, or about 0.5% to about 1.5% by weight of the topical composition, and / or wherein diethylene glycol monoethyl ether is about 0.1% to about 4% by weight, about 0.2% to about 3% by weight, about 0.5% to about 2% by weight, or about 0.5% to about 1.5% by weight of the topical composition. In some embodiments, the topical composition comprises about 1% to about 3.5% by weight of a penetration enhancer. In some embodiments, the topical composition comprises a combination of propylene glycol and diethylene glycol monoethyl ether, wherein propylene glycol is about 0.5% to about 2% by weight, and diethylene glycol monoethyl ether accounts for about 0.5% to about 2% by weight of the topical composition. In some embodiments, the topical composition comprises a combination of propylene glycol and diethylene glycol monoethyl ether, wherein propylene glycol is about 0.5% to about 1% by weight, and diethylene glycol monoethyl ether accounts for about 0.5% to about 1% by weight of the topical composition.

[0086] In some embodiments, after application, the topical composition dries quickly. For example, in some embodiments, after application, the topical composition dries within 120 seconds, within 90 seconds, within 80 seconds, within 70 seconds, within 60 seconds, or within 30 seconds.

[0087] In some embodiments, the spray-on topical composition consists essentially of: (a) about 0.05% to about 5% by weight of naftifine or a pharmaceutically acceptable salt thereof, (b) a film former comprising octylacrylamide acrylate copolymer, (c) a propellant, (d) an alcohol solvent, and (e) a penetration enhancer. In some embodiments, the topical composition described above does not comprise a hydrophilic polymer, such as a hydrophilic film-forming polymer.

[0088] In some embodiments, the spray-type topical composition comprises (a) about 0.05 wt % to about 5 wt % of naftifine or a pharmaceutically acceptable salt thereof, (b) about 1 wt % to about 5 wt % of a film former comprising octylacrylamide acrylate copolymer, (c) about 25 wt % to about 45 wt % of a propellant, (d) about 50 wt % to about 70 wt % of an alcohol solvent, and (e) about 1 wt % to about 3.5 wt % of a penetration enhancer.

[0089] The topical composition of the present invention can be applied by means known in the art. In some embodiments, the present disclosure provides a delivery device for applying the composition. In some embodiments, the present disclosure provides a delivery device comprising a topical composition as described herein. In some embodiments, the delivery device is a sealed and pressurized device, such as an aerosol container. In some embodiments, the delivery device is a sealed and pressurized device, i.e., an aerosol container having a member (e.g., an aerosol nozzle) for providing an aerosol spray of the topical composition. In some embodiments, the delivery device comprises the topical composition in an amount sufficient for a single application of the composition. In some embodiments, the delivery device comprises the topical composition in an amount sufficient for twice applying the composition. In some embodiments, the delivery device comprises the topical composition in an amount sufficient for three or more applications of the composition. In some embodiments, the present disclosure provides a kit, wherein the kit comprises one or more, such as two delivery devices. In one embodiment, the kit comprises two, three, four, five, six or more delivery devices, wherein one of the delivery devices is used as a whole for each application. In some embodiments, the kit comprises two aerosol cans, wherein the two aerosol cans comprise a topical composition as described herein, wherein one of the aerosol cans is used as a whole for each application. In some embodiments, the kit comprises one aerosol can containing a topical composition described herein in an amount sufficient to completely cover both feet. In some embodiments, the kit comprises two aerosol cans containing a topical composition described herein, each in an amount sufficient to completely cover one foot.

[0090] In embodiments where the delivery device is a pressurized device, the pressure in the sealed and pressurized device can be any pressure suitable for delivering the topical composition. In some embodiments, the pressure is from about 28 psi to about 145 psi at 25°C.

[0091] In some embodiments, the delivery device comprising the topical composition is an aerosol device having a member for providing an aerosol of the topical composition. As used herein, the aerosol device will include any device capable of producing fine aerosol droplets of the topical composition. In some embodiments, the aerosol device produces aerosol droplets of the topical composition having an average diameter of about 20 μm to about 150 μm. In some embodiments, the aerosol device produces aerosol droplets of the topical composition having an average diameter of less than 300 μm, less than 250 μm, less than 200 μm, less than 150 μm, less than 100 μm, less than 50 μm or less than 25 μm. In some embodiments, at least 99% of the droplets have a diameter of 100 μm and above. In some embodiments, at least 99% of the droplets have a diameter of 100 μm and below.

[0092] In some embodiments, the present disclosure provides an article of manufacture for treating a dermatophyte skin infection (e.g., tinea pedis or onychomycosis) in a subject in need thereof, the article of manufacture comprising (a) a sealed, pressurized container comprising (i) a topical composition as described herein, and (ii) means for providing an aerosol spray of the topical composition, and (b) instructions for using the topical composition for treating the dermatophyte skin infection.

[0093] Drug-Device Combinations

[0094] In some embodiments, the present disclosure provides a drug-device combination for dispensing a composition, the drug-device combination comprising a container, the container comprising a composition, the composition comprising naftifine or a pharmaceutically acceptable salt thereof; a film former, the film former comprising octylacrylamide acrylate copolymer; an alcohol solvent; and a propellant.

[0095] In some embodiments, the present disclosure provides a drug-device combination for dispensing a composition, the drug-device combination comprising a container, the container comprising a composition, the composition comprising about 0.05% by weight to about 5% by weight of naftifine or a pharmaceutically acceptable salt thereof; a film former, the film former comprising octylacrylamide acrylate copolymer; an alcohol solvent; and a propellant, wherein the ratio of the alcohol solvent to the propellant in the composition is about 1:1 to about 3:1 (w / w).

[0096] In some embodiments, the present disclosure provides a drug-device combination for dispensing a composition, the drug-device combination comprising a container, the container comprising a composition, the composition comprising naftifine or a pharmaceutically acceptable salt thereof; a film former, the film former comprising octylacrylamide acrylate copolymer; an alcohol solvent; and a propellant, wherein the ratio of the alcohol solvent to the propellant in the composition is about 1:1 to about 3:1 (w / w).

[0097] In some embodiments, the present disclosure provides a drug-device combination for dispensing a composition, the drug-device combination comprising a container, the container comprising a composition, the composition comprising about 0.05% by weight to about 5% by weight of naftifine or a pharmaceutically acceptable salt thereof; a film former, the film former comprising octylacrylamide acrylate copolymer.

[0098] In some embodiments, the drug-device combination provides for dispensing the composition from a container. In some embodiments, the drug-device combination provides for spraying the composition from a container. In some embodiments, the drug-device combination provides for both spraying and dispensing the composition from a container. In some embodiments, the drug-device combination forms a pressurized system. In some embodiments, the drug-device combination is a metered dose system. In some embodiments, the drug-device combination is a self-administered drug-device combination.

[0099] Various containers can be used to hold, store or contain the compositions disclosed herein in the drug-device combination. In some embodiments, the container can include a metal body, such as a body lined with a chemically inert coating material to avoid degradation of the composition due to any interaction between the body and the composition. In some embodiments, the container can include a plastic body, such as a body lined with a chemically inert coating material to avoid degradation of the composition due to any interaction between the body and the composition. In some embodiments, the container is a substantially rigid metal or plastic container suitable for containing a pressurized propellant that is located within the container and in contact with the product to be dispensed. In some embodiments, the container is an internally substantially rigid metal or plastic container suitable for containing a pressurized propellant that is located within an outer container made of the same material and away from contact with the product to be dispensed.

[0100] In some embodiments, the container body can be constructed of materials such as metal, glass, ceramic, polyester, polyethylene terephthalate (PET) or other polymers. In some embodiments, glass containers can be provided with a safety coating consisting of, for example, polypropylene to accommodate glass fragments that may be formed when impacting a hard surface. In some embodiments, a metal container body can be used to withstand impacts and adopt a surface coating. In some embodiments, the container comprises stainless steel, tinplate and aluminum or a combination thereof. In some embodiments, the aluminum is an aluminum alloy or anodized aluminum.

[0101] Various inert coating materials can be used to line the container body, including any suitable coating material known in the art, such as polymers, lacquers, resins or other coating treatments that create a barrier between the container and the composition to prevent any chemical interaction between the composition and the container. In some embodiments, the inert material is a non-metallic coating. In some embodiments, known coatings for metal containers include acrylic resins, phenolic resins, polyester resins, epoxy resins, and vinyl resins that can be used to line the container body of the drug-device combination disclosed herein. Thus, the container coating used with the composition of the present invention can be selected so that it does not itself exhibit acidic or alkaline reactivity and does not leach acidic or alkaline reacting impurities therefrom in the presence of the composition.

[0102] In some embodiments, the interior of the metal container may be lined with a material such as polyamide, polyimide, polypropylene, polyethylene, a fluoropolymer including perfluoroethylene propylene copolymer (FEP), fluororubber (FPM), ethylene-propylene diene monomer rubber (EPDM), polytetrafluoroethylene (PTFE), ethylene tetrafluoroethylene copolymer (EFTE), perfluoroalkoxyalkane, perfluoroalkoxyalkylene, or a blend of a fluoropolymer and a non-fluorocarbon polymer. Fluoropolymers may be used, for example, in combination with polyimide-polyamide resins.

[0103] The coating material of the container can be applied as a single layer or multiple layers, for example to allow each layer to cure before applying another layer. Applying more than one coating can be used to shield the composition from the metal container and prevent the active ingredient from adhering to the container wall.

[0104] In some embodiments, the drug-device combination comprises a pressurized system in which a composition to be dispensed as an aerosol is stored. The system can be pressurized, for example, by a propellant that is typically dissolved in the composition. The composition can be released from the container upon opening a pressure-actuated valve mechanism, for example, located in the top of the container.

[0105] In some embodiments, the drug-device combination disclosed herein comprises a valve assembly, which comprises a valve cup sometimes referred to as a mounting cup, a valve body or housing provided with a valve stem, a spring, a dip tube, and an actuator. In some embodiments, the valve assembly may also include a secondary shut-off valve for controlling the flow from the container, whereby when the sprayer is not in use, the composition flow cannot occur through the secondary valve and cannot leave the sprayer, and therefore contamination or evaporation of the composition in the container will not occur. In some embodiments, the valve assembly may be configured so that the operating part is held together by a snap-fit ​​configuration. In some embodiments, no screws or bolts are required and no fastening tools are required for constructing the valve assembly. In some embodiments, the parts of the valve assembly are snapped together piece by piece. In some embodiments, the actuator (also referred to as a trigger sprayer) may include two or more parts. In some embodiments, the actuator may include a trigger molded integrally with a manifold. In some embodiments, the trigger may also be used as a cover for the body of the actuator. In some embodiments, the trigger and the cover may include an integrally formed spring or an integrally formed living hinge. In some embodiments, the spring or living hinge can provide resistance when the trigger is actuated, and provide a force sufficient to disengage the manifold from the actuation of the valve when the force applied to the trigger during actuation is removed or reduced. In some embodiments, the spring or living hinge can include a geometric shape that can improve the function of the spring or living hinge. The actuator of the valve assembly can include a body or housing fixed to the top of the container body, and the actuator plunger or button is assembled in the housing. In some embodiments, the plunger or button can be assembled above or in the body in some way and connected to the valve stem or at least indirectly engage or actuate the valve stem.

[0106] In some embodiments, the actuator can be actuated by a squeezable actuator. In some embodiments, a pull tab can be used to actuate the actuator. In some embodiments, the actuator can include an extendable handle. In other embodiments, the actuator can include a timer. In other embodiments, the actuator can include an integrated hood or windshield. In some embodiments, the actuator can also include a selectable spray pattern. In some embodiments, the actuator can also include a locking mechanism.

[0107] In some embodiments, the actuator can be made of any desired material or material combination. In some embodiments, the actuator can be made of plastic or resin-based materials. In some embodiments, the actuator can include metal components. In other embodiments, flexible, extensible or other elastomeric materials can be used or integrated into the actuator design. In some embodiments, the actuator can be attached to, matched with, or otherwise assembled with a plastic or metal container having a valve.

[0108] In some embodiments, the actuator is coupled to a protruding stem of a valve mounted in the container and is adapted to be depressed by a user's finger to operate the associated valve and thereby allow release of the composition from the container. Optional materials for the valve stem are polyamide and acetal copolymers.

[0109] In some embodiments, the valve stem can be arranged so that the valve stem emerges through a central opening in the base portion of the mounting cup. In some embodiments, below the underside of the base is a washer that surrounds a lateral orifice in the hollow valve stem and is used to seal the orifice in the valve stem when the valve is in the closed position. The stem washer can be selected to withstand extreme chemical conditions and not soften, harden or crack within the valve. Any of these changes in the material may result in improper valve function and / or loss of seal and product leakage. In some embodiments, the stem washer is formed of rubber or other elastomeric material and is sized to seal against the outer surface of the valve stem.

[0110] A product channel is usually provided for guiding the released, distributed or sprayed composition outside the container and reaching the desired environment through the valve actuation assembly. In some embodiments, the drug-device combination disclosed herein comprises a product channel. In some embodiments, the product channel of the drug-device combination disclosed herein is a dip tube. In some embodiments, the dip tube can be integrated with the container body or button, or can be a separate structure communicated between the valve stem and the product dispensing orifice formed in the actuator. In some embodiments, the dip tube extends through the neck of the container and enters the fluid contents of the container. In some embodiments, the dip tube communicates the fluid supply passage of the container with the valve assembly. In some embodiments, the dip tube is a separate straw-like element. In some embodiments, the dip tube is produced by low-density polyethylene, medium-density polyethylene or high-density polyethylene or polypropylene thermoplastic material.

[0111] The liquid composition to be dispensed or sprayed from the container can be made to fill the pressure chamber and, when the pressure chamber is filled, push against a pressure piston supported by a spring disposed in the pressure chamber. Thus, when the user pumps liquid into the pressure chamber, this liquid pushes the pressure piston, which loads (compresses) the spring and thus places the liquid under pressure in the pressure chamber in a manner similar to the pressurized contents of the container. In an exemplary embodiment, such a pressure spring can be a spring in the broadest sense and can therefore be any elastic device that can store potential energy, including, for example, air or gas shock absorbers or springs, springs of various compositions and materials, etc.

[0112] Spray characterization (e.g., droplet size distribution (DSD) of the plume released after spraying) can be measured by appropriate analytical procedures under specified experimental and instrumental conditions, and validation and / or calibration known in the art. This includes, but is not limited to, photography, laser diffraction, and impaction systems (precipitation impaction, next generation impaction (NGI), etc.). Droplet size distribution can be determined based on the DSD of droplets larger than 10 mm. 90 The particle diameter designation "(D)" refers to the representative diameter at which 90% (D) of the total volume of the sprayed liquid is 90 )、50%(D 50 ) and 10% (D 10 ) is composed of droplets with a diameter less than or equal to the declared value. The spray characteristics can refer to the average or median value collected for multiple sprays. The multiple sprays can be at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more sprays.

[0113] In some embodiments, the drug-device combination is adapted to provide a spray comprising the composition, wherein the D 90 The droplet size is greater than 1 μm, greater than 10 μm, greater than 20 μm, greater than 30 μm, greater than 50 μm, greater than 70 μm, or greater than 100 μm. In some embodiments, the drug-device combination is suitable for providing a spray comprising the composition, wherein the spray has a D 90 The droplet size is less than 500 μm, less than 400 μm, less than 300 μm, or less than 200 μm. In some embodiments, when sprayed from the drug-device combination, the composition has a D 90 The droplet size is about 140 μm to about 170 μm. In some embodiments, when sprayed from the drug-device combination, the composition has a D 90 The droplet size is about 140 μm to about 145 μm. In some embodiments, when sprayed from the drug-device combination, the composition has a D 90 The droplet size is about 145 μm to about 150 μm. In some embodiments, when sprayed from the drug-device combination, the composition has a D 90 The droplet size is about 140 μm to about 150 μm. In some embodiments, when sprayed from the drug-device combination, the composition has a D 90 The droplet size is about 140 μm to about 160 μm. In some embodiments, when sprayed from the drug-device combination, the composition has a D 90 The droplet size is about 150 μm to about 160 μm. In some embodiments, when sprayed from the drug-device combination, the composition has a D 90The droplet size is about 150 μm to about 165 μm. In some embodiments, when sprayed from the drug-device combination, the composition has a D 90 The droplet size is about 160 μm to about 165 μm. In some embodiments, when sprayed from the drug-device combination, the composition has a D 90 The droplet size was about 165 μm to about 170 μm.

[0114] In some embodiments, when sprayed from the drug-device combination, the composition has an average D 90 The droplet size is about 155 μm to about 163 μm. In some embodiments, when sprayed from the drug-device combination, the average D 90 The droplet size is about 155 μm to about 160 μm. In some embodiments, when sprayed from the drug-device combination, the average D 90 The droplet size is about 160 μm to about 163 μm. In some embodiments, when sprayed from the drug-device combination, the average D 90 The droplet size is about 155 μm to about 157 μm. In some embodiments, when sprayed from the drug-device combination, the average D 90 The droplet size was about 157 μm to about 160 μm.

[0115] In some embodiments, the naftifine or a pharmaceutically acceptable salt thereof in the composition of the drug-device combination is naftifine hydrochloride. The concentration of naftifine in the composition of the drug-device combination can vary. In some embodiments, the concentration of naftifine in the composition of the drug-device combination is less than 5% by weight of the composition. In some embodiments, the concentration of naftifine in the composition of the drug-device combination is less than 4.5%, less than 4.0%, less than 3.5%, or less than 3.0% by weight of the composition. In some embodiments, the composition of the drug-device combination comprises about 0.05% to about 5% by weight of naftifine. In some embodiments, the composition of the drug-device combination comprises about 0.05 wt % to about 4 wt %, about 0.1 wt % to about 3.5 wt %, about 0.1 wt % to about 3.0 wt %, about 0.2 wt % to about 3.0 wt %, about 0.5 wt % to about 2.5 wt %, about 1.0 wt % to about 3.0 wt %, about 1.0 wt % to about 2.5 wt %, about 1.5 wt % to about 2.5 wt %, about 1.8 wt % to about 2.2 wt %, or about 2.0 wt % of naftifine.

[0116] The present disclosure provides a drug-device combination comprising a topical composition for application. In some embodiments, the present disclosure provides an aerosol spray composition from a drug-device combination for application. In some embodiments, the term aerosol spray composition is a pressurized composition, such as a composition in a closed container under pressure, so that an aerosol can be formed when released from the container in the drug-device combination. In some embodiments, a drug-device combination may include a pressurized or unpressurized composition. For example, the term "topical composition" may include (i) a liquid composition inside a pressurized container, which becomes an aerosol spray when discharged from the container, and (2) an aerosol spray discharged from the container. Additionally, in some embodiments, the term "topical composition" may include a liquid composition on a surface (e.g., a skin surface), which forms the liquid composition when the aerosol spray contacts the surface. In some embodiments, applying an aerosol spray from the drug-device combination provides a more consistent composition application to the subject being treated. In some embodiments, applying an aerosol spray from the drug-device combination provides a more thorough composition application to the subject, such as covering a larger area. In some embodiments, applying an aerosol spray from the drug-device combination provides a more convenient method of application. In some embodiments, applying an aerosol spray from the drug-device reduces the need for other applicators, such as wipes, gauze, fabric, etc. In some embodiments, applying an aerosol spray from the drug-device combination reduces exposure of the hands or other unintended body parts to the presence of naftifine that can occur through application in a cream, gel, or liquid. In some embodiments, applying an aerosol spray from the drug-device combination provides a more convenient mode of application because it allows for rapid drying of the composition after application.

[0117] Treatment

[0118] The topical compositions and drug-device combinations described herein can be used to treat dermatophyte skin infections. The term "dermatophyte skin infection" can refer to any skin condition caused by a dermatophyte, including, for example, Microsporum, Trichophyton, and Epidermophyton fungal species. In some embodiments, the term "dermatophyte skin infection" refers to tinea pedis, interdigital tinea pedis, tinea cruris, tinea corporis, and / or tinea capitis. In some embodiments, the term "dermatophyte skin infection" refers to tinea pedis, interdigital tinea pedis, or tinea cruris. In some embodiments, the present disclosure provides a method of treating a dermatophyte skin infection in a subject in need thereof, the method comprising topically applying to the subject a topical composition of any topical spray composition described herein.

[0119] Topical compositions and drug-device combinations as described herein can be used to treat onychomycosis. The term "onychomycosis" refers to a fungal infection of one or more fingernails (e.g., toenails) of a subject, causing the fingernails to change color, thicken, and / or separate from the nail bed. In certain embodiments, onychomycosis refers to a brittle, fragile, or uneven fingernail caused by a fungal infection. In certain embodiments, onychomycosis refers to a deformed shape of a fingernail caused by a fungal infection. In certain embodiments, onychomycosis begins with a fungal infection in the skin, such as from tinea pedis. In certain embodiments, onychomycosis is caused by a weakened immune system, reduced blood circulation (e.g., due to diabetes) or age.

[0120] As used herein, the terms "treatment" and "alleviation" of dermatophyte skin infections refer to reducing the severity of symptoms associated with dermatophyte skin infections. Therefore, in some embodiments, the methods provided herein provide palliative care. In some embodiments, the term "treatment" refers to eliminating symptoms associated with dermatophyte skin infections. Therefore, in some embodiments, the methods provided herein provide curative care. In some embodiments, the symptoms associated with dermatophyte skin infections include one or more of the following: itching, burning, blanching or cracking, desquamation, blistering, inflammation, pustules or ulcers of the skin. In some embodiments, the methods described herein reduce and / or eliminate the severity of one, two, three or more than three symptoms associated with dermatophyte skin infections.

[0121] As used herein, the term "treatment" and "alleviation" of onychomycosis refers to reducing the severity of the symptoms associated with onychomycosis. Therefore, in some embodiments, the method provided herein provides palliative care for onychomycosis. In some embodiments, the term "treatment" refers to eliminating the symptoms associated with onychomycosis. Therefore, in some embodiments, the method provided herein provides curative care associated with onychomycosis. In some embodiments, the method described herein reduces and / or eliminates the severity of one, two, three or more than three symptoms associated with onychomycosis.

[0122] In some embodiments, the treatment methods described herein provide increased mycological cure rates. As used herein, the term mycological cure rate indicates the percentage of samples collected (skin scrapings from tinea pedis lesions) that have (a) negative KOH staining after microscopic examination; and (b) negative fungal culture results.

[0123] In some embodiments, the composition has a mycological cure rate of at least 20% at a single dose of treatment, at least 30% at a single dose of treatment, at least 40% at a single dose of treatment, at least 50% at a single dose of treatment, at least 60% at a single dose of treatment, at least 70% at a single dose of treatment, or at least 80% at a single dose of treatment. In some embodiments, the composition has a mycological cure rate of at least 20% at two doses of treatment, at least 30% at two doses of treatment, at least 40% at two doses of treatment, at least 50% at two doses of treatment, at least 60% at two doses of treatment, at least 70% at two doses of treatment, or at least 80% at two doses of treatment. Mycological cure rates are determined by defining cure as negative KOH staining using microscopy and negative fungal cultures of skin scrapings obtained from lesions six weeks after treatment.

[0124] In some embodiments, the complete clinical cure rate of the composition is at least 20% at a single dose of treatment, at least 30% at a single dose of treatment, at least 40% at a single dose of treatment, at least 50% at a single dose of treatment, at least 60% at a single dose of treatment, at least 70% at a single dose of treatment, or at least 80% at a single dose of treatment. In some embodiments, the complete clinical cure rate of the composition is at least 20% at two doses of treatment, at least 30% at two doses of treatment, at least 40% at two doses of treatment, at least 50% at two doses of treatment, at least 60% at two doses of treatment, at least 70% at two doses of treatment, or at least 80% at two doses of treatment. Complete clinical cure rate is defined as the absence of erythema, scaling, and pruritus six weeks after treatment. .

[0125] In some embodiments, the therapeutic efficacy of the composition is at least 20% at a single dose of treatment, at least 30% at a single dose of treatment, at least 40% at a single dose of treatment, at least 50% at a single dose of treatment, at least 60% at a single dose of treatment, at least 70% at a single dose of treatment, or at least 80% at a single dose of treatment. In some embodiments, the therapeutic efficacy of the composition is at least 20% at two doses of treatment, at least 30% at two doses of treatment, at least 40% at two doses of treatment, at least 50% at two doses of treatment, at least 60% at two doses of treatment, at least 70% at two doses of treatment, or at least 80% at two doses of treatment. Efficacy is defined as negative KOH staining, negative fungal culture, and absence or mild erythema, scaling, and pruritus six weeks after treatment.

[0126] In some embodiments, the complete clearance of the composition is at least 20% at a single dose of treatment, at least 30% at a single dose of treatment, at least 40% at a single dose of treatment, at least 50% at a single dose of treatment, at least 60% at a single dose of treatment, at least 70% at a single dose of treatment, or at least 80% at a single dose of treatment. In some embodiments, the complete clearance of the composition is at least 20% at two doses of treatment, at least 30% at two doses of treatment, at least 40% at two doses of treatment, at least 50% at two doses of treatment, at least 60% at two doses of treatment, at least 70% at two doses of treatment, or at least 80% at two doses of treatment. Complete clearance is defined as negative KOH stain, negative fungal culture, and complete absence of erythema, desquamation, and pruritus six weeks after treatment. Those skilled in the art will understand that not all subjects will respond equally to the methods described herein. Therefore, when referring to treatments that reduce and / or eliminate symptoms, the skilled person can understand any statistical significance of the clinical results associated with the present invention and is within the scope of the present invention. Those skilled in the art will also understand that "treatment" can depend on the frequency of administration, the amount of active agent administered, the disposition of the subject being treated (e.g., age, condition, sex, height, weight, underlying health condition, etc.). In some embodiments, the methods provided herein provide "treatment" for dermatophyte skin infections or onychomycosis in a population of subjects, wherein the treatment provides a reduction in the severity of symptoms associated with dermatophyte skin infections or onychomycosis and / or an elimination of symptoms associated with dermatophyte skin infections or onychomycosis in greater than 30%, greater than 40%, greater than 50%, greater than 60%, or greater than 70% of the subjects in the population.

[0127] In some embodiments, the topical composition is applied to the infected area and healthy surrounding skin. In some embodiments, the topical composition is distributed from an aerosol can as a local film-forming spray and is applied to both feet in a single case (each single application), even if only one foot has signs and symptoms of infection. A single continuous spray is intended to cover the lesion skin and healthy adjacent skin between and around the toes and the bottom and side of each foot. For example, in some embodiments, the topical composition is applied so that the entire affected area is covered by the topical composition. In some embodiments, the topical composition covers more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90% or more than 95% in the affected area. In some embodiments, when the infection affects a specific body part (e.g., foot), the topical composition is applied to the entire body part. For example, in some embodiments, the topical composition can be applied to the area exceeding the affected area. For example, in some embodiments, when a dermatophyte skin infection affects the feet, then the topical composition may be applied to more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or more than 95% of the feet. The same would be true for any other specific body part affected by a dermatophyte skin infection. Thus, in some embodiments, the topical composition may cover both feet, even if there is no infection on the applied area.

[0128] In some embodiments, the disclosure provides a topical composition that needs to reduce the frequency of application to treat dermatophyte skin infections. For example, in some embodiments, the composition is applied no more than once in a three-day period. In some embodiments, the composition is applied no more than once in a four-day period, no more than once in a five-day period, no more than once in a six-day period, no more than once in a seven-day (1 week) period, no more than once in a ten-day period, or no more than once in a fourteen-day (2 week) period. In some embodiments, the composition is applied no more than once.

[0129] In some embodiments, the present disclosure provides topical compositions that require a reduced number of applications to treat dermatophyte skin infections or onychomycosis. In some embodiments, the topical composition is applied to the subject no more than once during treatment to relieve the dermatophyte skin condition or onychomycosis. In some embodiments, the topical composition is applied to the subject no more than twice to relieve the dermatophyte skin condition or onychomycosis. In some embodiments, the topical composition is applied to the subject no more than three, four, or five times to relieve the dermatophyte skin condition or onychomycosis.

[0130] In some embodiments, where more than one application is desired, various application regimens may be used. In some embodiments, the methods described herein comprise a first application of the topical composition and a second application of the topical composition. In some embodiments, the second application of the composition is 5 to 10 days after the first application. In some embodiments, the second application of the composition is 6 to 9 days, 7 to 8 days, or about 7 days after the first application.

[0131] The effectiveness of treating dermatophyte skin conditions can be determined by methods known to those skilled in the art. For example, in some embodiments, the effectiveness of treating dermatophyte skin conditions can be determined by: (a) comparing clinical signs and symptoms associated with tinea pedis in (i) subjects treated with the topical composition to (ii) subjects treated with a placebo; and / or (b) comparing mycological cure rates (i.e., potassium hydroxide staining and fungal culture results) in (i) subjects treated with the topical composition to (ii) subjects treated with a placebo.

[0132] In some embodiments, efficacy is measured using mycological cure (KOH and fungal culture), efficacy (defined as negative KOH stain, negative fungal culture, and absence or mild erythema, scaling, and pruritus), and clinical cure (defined as absence of erythema, scaling, and pruritus). In some embodiments, the primary efficacy endpoint is complete clearance at day 42, defined as negative KOH, negative fungal culture, and absence of individual signs and symptoms (i.e., erythema, scaling, and pruritus). In some embodiments, the percentage of subjects who applied the topical composition achieved the primary efficacy endpoint, i.e., twice the percentage of subjects who applied placebo or received no treatment.

[0133] In some embodiments, the topical composition provides low systemic exposure to naftifine. In some embodiments, the systemic level of naftifine after a single application of the topical spray composition averages about 10 pg / mL to about 250 pg / mL or about 50 pg / mL to about 150 pg.mL after 4 weeks. In some embodiments, the systemic level of naftifine after a single application of the topical spray composition averages about 100 pg / mL after 4 weeks.

[0134] In some embodiments, the present disclosure provides a method of treating a dermatophyte skin infection in a patient, the method comprising administering to the subject two doses of a topical composition comprising naftifine, wherein the topical composition is a monophasic solution and the naftifine is present at at least 80% saturation under conditions of use, wherein the second dose is administered about 1 week after the first dose. In some embodiments, the dermatophyte skin condition is tinea pedis, interdigital tinea pedis, or tinea cruris. In some embodiments, the present disclosure provides a method of treating onychomycosis in a patient, the method comprising administering to the subject two doses of a topical composition comprising naftifine, wherein the topical composition is a monophasic solution and the naftifine is present at at least 80% saturation under conditions of use, wherein the second dose is administered about 1 week after the first dose.

[0135] In some embodiments, the present disclosure provides a method for maintaining naftifine in the stratum corneum of a subject at a therapeutic level to alleviate symptoms associated with dermatophyte skin conditions. In some embodiments, a peeling assay is used to measure the therapeutic level of naftifine in the stratum corneum. In some embodiments, the therapeutic level of naftifine comprises a naftifine tape stripping concentration of greater than 10,000 pg / mL, greater than 12,000 pg / mL, or greater than 15,000 pg / mL. In some embodiments, the therapeutic level is at least 10,000 pg / mL. In some embodiments, the therapeutic level is maintained for at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks.

[0136] In some embodiments, the present disclosure provides a method for maintaining therapeutic levels of naftifine in the stratum corneum of a subject for four weeks, the method comprising administering to the subject two doses of a topical composition comprising naftifine, wherein the composition is a monophasic solution and the drug is present at at least 80% of saturation under conditions of use, wherein the second dose is administered about 1 week after the first dose.

[0137] In some embodiments, four weeks after the first dose and three weeks after the second dose, the amount of naftifine in the stratum corneum of the subject is, on average, half the amount extracted at the second dose.

[0138] In some embodiments, the present disclosure provides a method of treating a dermatophyte skin infection in a subject in need thereof, the method comprising administering a topical composition, wherein said administering the topical composition to the subject achieves at least a 10% success rate, at least a 20% success rate, at least a 30% success rate, at least a 40% success rate, at least a 50% success rate, at least a 60% success rate, at least a 70% success rate, or at least an 80% success rate for an efficacy endpoint.

[0139] Various efficacy endpoints are known to those skilled in the art, wherein the primary efficacy endpoint in a clinical trial is to achieve complete clearance. In some embodiments, complete clearance is measured at day 21, day 28, day 35, day 42, day 47, or day 54. In some embodiments, complete clearance is measured at day 42. Complete clearance can be defined as KOH negative, fungal culture negative, and / or a score of 0 'none' for individual signs and symptoms selected from erythema, desquamation, and pruritus. In some embodiments, the efficacy endpoint is to achieve complete clearance at day 42, wherein complete clearance is defined as KOH negative, fungal culture negative, and / or a score of 0 'none' for individual signs and symptoms selected from erythema, desquamation, and pruritus.

[0140] In some embodiments, the present disclosure provides a method of treating a dermatophyte skin infection in a subject in need thereof, the method comprising administering a topical composition comprising 2% naftifine or a pharmaceutically acceptable salt thereof, wherein the topical composition is administered to the subject in two doses, wherein the second dose is administered about 1 week after the first dose, wherein the administering of the topical composition to the subject achieves at least a 50% success rate for an efficacy endpoint. In some embodiments, the dermatophyte skin condition is tinea pedis, interdigital tinea pedis, or tinea cruris.

[0141] In some embodiments, the topical composition is administered to a population of subjects. In some embodiments, the percentage of subjects administered the topical composition achieves the primary efficacy endpoint, which is twice the percentage of subjects administered a placebo.

[0142] In some embodiments, the primary efficacy endpoint is a measure of mycological cure, efficacy, and complete clearance defined as KOH negativity, fungal culture negativity, and absence of individual signs and symptoms selected from erythema, scaling, and pruritus.

[0143] In some embodiments, the present disclosure provides a method of treating onychomycosis in a subject in need thereof, the method comprising administering a topical composition, wherein the administering of the topical composition to the subject achieves at least a 10% success rate, at least a 20% success rate, at least a 30% success rate, at least a 40% success rate, at least a 50% success rate, at least a 60% success rate, at least a 70% success rate, or at least an 80% success rate for an efficacy endpoint. Onychomycosis is a fungal infection of the nail that causes discoloration, thickening, and separation from the nail bed.

[0144] In some embodiments, the efficacy endpoint associated with onychomycosis is at least a 50% reduction, at least an 80% reduction, or at least a 90% reduction in one or more symptoms associated with onychomycosis (e.g., discoloration, thickening, and / or separation of the nail from the nail bed, brittle, crumbly, or uneven nails). In some embodiments, the efficacy endpoint is determined 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after the last application of the topical spray.

[0145] In some embodiments, the efficacy endpoint associated with mycological cure is greater than 40%, greater than 50%, or greater than 60%. In some embodiments, the efficacy endpoint associated with mycological cure is about 40% to about 80% or about 50% to about 70%.

[0146] In some embodiments, the efficacy endpoint associated with complete clinical cure is greater than 20%, greater than 25%, or greater than 300%. In some embodiments, the efficacy endpoint associated with mycological cure is about 20% to about 50% or about 25% to about 40%.

[0147] In some embodiments, the efficacy endpoint associated with therapeutic efficacy is greater than 40%, greater than 45%, or greater than 50%. In some embodiments, the efficacy endpoint associated with therapeutic efficacy is about 40% to about 80% or about 45% to about 70%.

[0148] In some embodiments, the efficacy endpoint associated with complete clearance is greater than 5%, greater than 10%, or greater than 50%. In some embodiments, the efficacy endpoint associated with mycological cure is about 5% to about 40% or about 10% to about 35%.

[0149] In some embodiments, the present disclosure provides a method of treating a dermatophyte skin infection in a subject, the method comprising administering a topical composition comprising naftifine, wherein the composition is a monophasic solution and the drug is present at at least 80% saturation under conditions of use, wherein the administering of the topical composition to the subject achieves complete clearance of the signs and symptoms of tinea pedis, wherein complete clearance is defined as achieving the following scores listed below for all clinical signs and symptoms:

[0150] (a) On day 42, the severity of erythema decreased relative to baseline, with a score of 0;

[0151] (b) On day 42, the severity of desquamation decreased relative to baseline, with a score of 0;

[0152] (c) on day 42, the severity of pruritus decreased relative to baseline, with a score of 0;

[0153] And mycological clearance was achieved in KOH test and mycological culture.

[0154] In some embodiments, the dermatophyte skin condition is tinea pedis, interdigital tinea pedis, or tinea cruris.

[0155] In some embodiments, after a single application of the naftifine topical composition, the arithmetic mean AUC of naftifine is t(pg*h / mL) is no more than 300,000 pg*h / mL, no more than 250,000 pg*h / mL, or no more than 200,000 pg*h / mL.

[0156] In some embodiments, after a single application of the naftifine topical composition, the C of naftifine is max (pg / mL) is no more than 3000 pg / mL, no more than 2500 pg / mL, no more than 2000 pg / mL, no more than 1500 pg / mL or no more than 1000 pg / mL.

[0157] In some embodiments, the median Tmax (hours) of naftifine after a single application of the naftifine topical composition is 12 hours, 18 hours, 24 hours, 30 hours, or 36 hours.

[0158] In some embodiments, the present disclosure provides a method of treating a dermatophyte skin infection or onychomycosis in a subject in need thereof, the method comprising applying an aerosol spray or mist to the skin using the drug-device combination disclosed herein. In some embodiments, the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris.

[0159] In some embodiments, the composition of the drug-device combination is applied to the site of infection. For example, in some embodiments, the composition of the drug-device combination is applied so that the spray droplet size (D 90 ), the composition covers the entire affected area. In some embodiments, a spray droplet size (D 90 ), the composition covers greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90% or greater than 95% of the affected area.

[0160] In some embodiments, the present disclosure provides compositions administered from the drug-device combinations described herein that require reduced frequency of application to treat dermatophyte skin infections. For example, in some embodiments, using a spray droplet size (D 90 ), the composition is applied no more than once within a three-day period. In some embodiments, a spray droplet size (D 90 ), the composition is administered no more than once within a four day period, no more than once within a five day period, no more than once within a six day period, no more than once within a seven day (1 week) period, no more than once within a ten day period, or no more than once within a fourteen day (2 week) period.

[0161] In some embodiments, a spray droplet size (D 90 ), the present disclosure provides a composition dispensed from a drug-device combination that requires a reduced number of applications to treat dermatophyte skin infections or onychomycosis. In some embodiments, a spray droplet size (D 90 ) such that no more than one application to the subject during the course of treatment is sufficient to provide relief from a dermatophyte skin condition or onychomycosis. In some embodiments, the composition is applied to the subject no more than twice to provide relief from a dermatophyte skin condition or onychomycosis. In some embodiments, the composition is applied to the subject no more than three, four, or five times to provide relief from a dermatophyte skin condition or onychomycosis.

[0162] In some embodiments, where more than one administration is desired, various administration regimens may be used. In some embodiments, the methods described herein comprise a first administration of the composition and a second administration of the composition. In some embodiments, the second administration of the composition is 5 to 10 days after the first administration. In some embodiments, the second administration of the composition is 6 to 9 days, 7 to 8 days, or about 7 days after the first administration.

[0163] It is important that the composition dries quickly after application to prevent dripping and running off. In some embodiments, the composition of the drug-device combination dries quickly after application. In some embodiments, the composition dries in less than three minutes after application to the skin. In some embodiments, the composition dries in less than two minutes after application to the skin. In some embodiments, the composition dries in less than one minute after application to the skin. For example, in some embodiments, using a spray droplet size (D 90 ), the composition of the drug-device combination dries within 120 seconds, within 90 seconds, within 80 seconds, within 70 seconds, within 60 seconds, or within 30 seconds after application. In some embodiments, at room temperature and at 1 atmosphere, after 500 μL, 250 μL, 100 μL, or 50 μL of the composition is applied to the skin, the composition dries within 90 seconds, within 80 seconds, within 70 seconds, or within 60 seconds.

[0164] All references cited herein, including patents, patent applications, articles, textbooks, etc., and references cited herein, to the extent they have not already been cited, are hereby incorporated by reference in their entirety.

[0165] Examples

[0166] Example 1 - Topical Naftifine Compositions: Various Film Forming Agents

[0167] As outlined in Tables 1 and 2, various topical compositions comprising 2% naftifine were prepared.

[0168] Table 1

[0169]

[0170] Table 2

[0171]

[0172] The samples were then analyzed for (i) visual precipitation, (ii) penetration of naftifine, (iii) antifungal efficacy, (iv) resistance of the resulting films to water and artificial sweat (pH 4.0 and 6.5) 24 hours after application, and (v) drying time. The results are presented in Tables 3 and 4.

[0173] Table 3

[0174]

[0175] Table 4

[0176]

[0177] The following terms used above may be defined as follows: Penetration Rating: 1 = Highest. Antifungal Efficacy: 1 = Maximum Killing. (i) Resistance: "+" indicates that the composition is resistant to the condition, "x" indicates that the composition is not resistant to the condition. Testing was performed in water at pH 7.0, pH 4.0 and pH 6.5.

[0178] As revealed from Tables 3 and 4, Sample 9 exhibited the shortest drying time while having good antifungal activity and skin penetration as well as high resistance to both water and artificial sweat.

[0179] Example 2 - Topical Naftifine Compositions: Various Solvent:Propellant Ratios

[0180] Various topical compositions containing naftifine were prepared by varying the amounts of ethanol and propellant as outlined in Table 5. Various compositions were sprayed on artificial skin and the following parameters were tested: appearance of spray during discharge, film formation time (assessed by appearance of film, complete drying time).

[0181] Table 5

[0182]

[0183] As revealed from Table 5, favorable film formation times (assessed by film appearance and through drying time) were obtained with a composition having about 60% ethanol and about 30% propellant (ie, an alcohol solvent:propellant ratio of 1.8:1).

[0184] Example 3 - Topical Naftifine Composition

[0185] Based on Sample 9 from Example 1, a topical composition (F5) comprising naftifine was prepared as outlined in Table 6.

[0186] Table 6

[0187]

[0188] Example 4 - Skin Penetration - Tape Strip Study in Human Subjects

[0189] The presence of naftifine in the stratum corneum (SC) was assessed after two applications of F5 (Sample 9 from Example 1) and F3 (Sample 11 from Example 1) to the forearms of 10 healthy adults on Day 1 and Day 8. Tape stripping of the skin was performed to quantify naftifine levels at time points up to 28 days after the initial application. Compared to F5 applied on Day 1 and Day 8, 2% F3 applied once daily The median naftifine skin level was higher with the cream applied for 14 days. By day 29, the naftifine levels in the skin after two applications of F5 were at least similar to those after daily application of Levels achieved after 2 weeks. This study demonstrated that sustained naftifine levels in the skin were measurable up to 29 days following a dosing regimen of F5.

[0190] Table 7: Summary of Naftifine Amounts in Tape Strips by Study Day

[0191]

[0192] F3 and F5 - single actuation applied topically on days 1 and 8

[0193] 2% cream (Sebela International Ltd) - single topical application on days 1 to 14

[0194] Example 5 - Proof of Concept Clinical Study - Naftifine Film-Forming Aerosol, 2% - F5

[0195] A randomized, double-blind, placebo-controlled, parallel-group study using F5 as a topical composition was conducted. F5 (N=42) and placebo (N=40) were administered once to subjects experiencing interdigital tinea pedis. The severity of the clinical signs and symptoms of the subjects' disease was rated on Days 14, 28, and 42, while mycological cure was assessed on Day 42. The results of Day 42 of the experiment are shown in Table 8.

[0196] Table 8

[0197]

[0198] Clinical results revealed that F5 was significantly superior to placebo in the efficacy endpoints tested.

[0199] Example 6: Dermal Penetration and Toxicity Studies in Hanford Minipigs

[0200] F1 (Sample 7 from Example 1), F3 (Sample 11 from Example 1), F4 (Sample 15 from Example 1), and F5 were each topically applied twice to a group of Hanford minipigs on days 1 and 8. The study did not produce test article-related effects on any organ or system. After a single application (2 ml / kg), systemic levels of naftifine were detectable in all treated minipigs as early as 0.5 hours after application, reaching a peak between 6-16 hours after application. After the second application of F5, little accumulation was observed, and there were no significant gender differences in dermal uptake by either application. Based on the lack of adverse evidence from the study, all naftifine formulations tested at concentrations are considered safe in Hanford minipigs when applied dermally twice a week apart at a dose level of 2 ml / kg to 10% of body surface area. The average data from this study are presented in Table 9 below, which reveals that F5 has the lowest systemic absorption in the minipig animal model.

[0201] Table 9

[0202]

[0203] Example 7: Naftifine levels in blood after a single application of F5 in human subjects

[0204] Naftifine levels in the blood after a single application of F5 were determined in 7 human subjects. The values ​​obtained were as follows: Arithmetic mean AUC t (h*pg / mL)-183,425; C max (pg / mL) -1051; Median Tmax (hours): 24.

[0205] Example 8: Chemical and physical stability of a topical composition containing naftifine (F5)

[0206] Chemical and physical stability parameters of the naftifine compositions were evaluated at 25°C and 60% relative humidity (referred to as "RT conditions") or 40°C and 75% relative humidity (referred to as "accelerated (ACC) conditions") for specific durations of T0 and 6 months.

[0207] The topical composition containing naftifine (F5) exhibited both physical and chemical stability, with no significant changes in the naftifine assay (100% at T=0, 99.5% after 6 months at RT, and 98.2% after 6 months under accelerated conditions) and the level of related compounds (total) was less than 0.07% at T=0 and after 6 months at RT and under accelerated conditions. See Table 10.

[0208] Table 10:

[0209]

[0210] nd: Not detected

[0211] The data presented demonstrate that the naftifine formulations described herein are not only more stable and more suitable for spray application, but the same formulations are effective in treating dermatophyte skin infections in vivo. The composition allows the active substance to stay on the skin for a long period of time, which provides sufficient time to treat dermatophyte skin infections by reducing the number of applications (e.g., only one or only two applications). The one or two application regimens enhance patient compliance compared to the current regimen of daily application for 14 days.

[0212] Example 9: Measurement of droplet size distribution of compositions sprayed from drug-device combinations

[0213] A 2% naftifine composition was prepared according to the formulation disclosed in Example 1. The prepared naftifine composition was placed and sealed in a drug-device combination as described herein. The measurement system equipment was used to measure the droplet size distribution (DSD) generated by the spray and the aerosol generated by the drug-device combination. Each composition was actuated to spray five times at a distance of 15 cm. The average values ​​of the DSD of the spray are shown in Table 11 below.

[0214] Table 11

[0215]

Claims

1. A spray-type topical composition comprising: a. about 0.05% to about 5% by weight of naftifine or a pharmaceutically acceptable salt thereof, b. a film former comprising an octyl acrylamide acrylate copolymer; c. alcohol solvent; and d. Propellant, The ratio of the alcohol solvent to the propellant in the composition is about 1:1 to about 3:1 (w / w).

2. The topical composition according to claim 1, wherein the naftifine or a pharmaceutically acceptable salt thereof is naftifine hydrochloride.

3. The topical composition of claim 1 or 2, wherein the composition comprises from about 1% to about 3% of naftifine or a pharmaceutically acceptable salt thereof.

4. The topical composition of claim 3, wherein the composition comprises about 2% naftifine or a pharmaceutically acceptable salt thereof.

5. The topical composition of any one of claims 1 to 4, wherein the composition comprises from about 2% w / w to about 10% w / w octylacrylamide acrylate copolymer.

6. The topical composition of claim 5, wherein the composition comprises from about 2% w / w to about 4% w / w octylacrylamide acrylate copolymer.

7. The topical composition according to any one of claims 1 to 6, wherein the ratio of film former to alcohol solvent in the composition is about 1:15 to 1:30 (w / w).

8. The topical composition of claim 7, wherein the ratio of film former to alcohol solvent in the composition is about 1:18 to 1:22 (w / w).

9. A topical composition according to any one of claims 1 to 8, wherein the composition comprises less than 4% of a hydrophilic polymer.

10. A topical composition according to any one of claims 1 to 9, wherein the composition comprises less than 0.5% of a hydrophilic polymer.

11. A topical composition according to any one of claims 1 to 10, wherein the alcohol solvent is C 1-6 alcohol.

12. The topical composition according to claim 11, wherein the C 1-6 The alcohol is methanol, ethanol, propanol, n-propanol, isopropanol, n-butanol, tert-butanol, 2-butanol, isobutanol, pentanol, hexanol, cyclohexanol or a combination thereof.

13. The topical composition of any one of claims 1 to 12, wherein the alcohol solvent has a viscosity of about 1 cp to about 150 cp.

14. The topical composition of any one of claims 1 to 13, wherein the composition comprises from about 10% to about 70% by weight of an alcohol solvent.

15. The topical composition of any one of claims 1 to 13, wherein the composition comprises from about 50% to about 70% by weight of an alcohol solvent.

16. A topical composition according to any one of claims 1 to 13, wherein the composition comprises less than 70% by weight of an alcohol solvent.

17. The topical composition of any one of claims 1 to 16, wherein the composition has a viscosity of from about 0.1 cp to about 500 cp.

18. The topical composition of claim 17, wherein the composition has a viscosity of from about 1 cp to about 150 cp.

19. The topical composition of any one of claims 1 to 18, wherein the propellant is a hydrocarbon propellant, a fluorocarbon propellant, a hydrofluorocarbon propellant, or a combination thereof.

20. The topical composition of claim 19, wherein the propellant is propane, isobutane, n-butane, isopentane, n-pentane, or a combination thereof.

21. The topical composition of claim 19, wherein the propellant is a hydrofluorocarbon propellant.

22. The topical composition of claim 19, wherein the hydrofluorocarbon propellant is 1,1,1,2-tetrafluoroethane (Norflurane 134A) or 1,1-difluoroethane (HFA-152a).

23. The topical composition of any one of claims 1 to 22, wherein the composition comprises from about 10% to about 50% by weight of propellant.

24. The topical composition of claim 23, wherein the composition comprises from about 25% to about 45% by weight of the propellant.

25. The topical composition of any one of claims 1 to 24, wherein the ratio of the alcohol solvent to the propellant is from about 1.5:1 to about 2.5:1 (w / w).

26. The topical composition of any one of claims 1 to 24, wherein the ratio of the alcohol solvent to the propellant is about 1:1 to 2:1 (w / w).

27. The topical composition of any one of claims 1 to 24, wherein the ratio of the alcohol solvent to the propellant is about 2:1 to 3:1 (w / w).

28. A topical composition according to any one of claims 1 to 27, wherein the ratio of film former to propellant is from about 1:7 to 1:15 (w / w).

29. The topical composition of claim 28, wherein the ratio of film former to propellant is about 1:8 to 1:12 (w / w).

30. The topical composition of any one of claims 1 to 29, further comprising a penetration enhancer, a solubilizer, an emulsifier, a solubilizer, or a combination thereof.

31. The topical composition of claim 30, wherein the penetration enhancer is a mixture of diethylene glycol monoethyl ether, diethyl sebacate, diisopropyl adipate, dimethyl isosorbide, dimethyl sulfoxide, polyethylene glycol, oleic acid, lactic acid esters, oleyl alcohol, alkyl glycosides, sugar alkyl esters, dimethylformamide, isopropyl myristate, Tween 80, sodium lauryl sulfate, oleic acid and octyl dimethyl para-aminobenzoic acid, or a combination thereof.

32. The topical composition of claim 30, wherein the penetration enhancer is a combination of propylene glycol and diethylene glycol monoethyl ether.

33. The topical composition of any one of claims 30 to 32, wherein the composition comprises from about 0.1% to about 7% (w / w) of a penetration enhancer.

34. The topical composition of claim 33, wherein the composition comprises from about 0.5% to about 2.5% (w / w) of a penetration enhancer.

35. A spray-type topical composition comprising: a. about 0.05% to about 5% by weight of naftifine or a pharmaceutically acceptable salt thereof; b. a film former comprising an octyl acrylamide acrylate copolymer; c. about 50 wt % to about 80 wt % alcohol solvent; and d. From about 15% to about 45% by weight of propellant.

36. A spray-type topical composition comprising: a. from about 0.05% to about 5% by weight of naftifine or a pharmaceutically acceptable salt thereof, b. from about 1 wt % to about 5 wt % of a film former comprising octylacrylamide acrylate copolymer, c. from about 15% to about 45% by weight of a propellant, d. from about 50% to about 80% by weight of an alcohol solvent, and e. From about 1 wt % to about 3.5 wt % of a penetration enhancer.

37. A spray-type topical composition comprising: a. from about 0.05% to about 5% by weight of naftifine or a pharmaceutically acceptable salt thereof, b. a film former comprising an octyl acrylamide acrylate copolymer; c. alcohol solvent; and d. Propellant, wherein the film formation time is less than about 30 seconds.

38. A delivery device comprising the topical composition of any one of claims 1 to 37.

39. The delivery device of claim 38, wherein the delivery device is an aerosol spray formulation.

40. The delivery device of claim 38, wherein the pressure inside the delivery device is from about 28 psi to about 145 psi at 25°C.

41. A delivery device according to any one of claims 38 to 40, wherein the delivery device comprises means for providing an aerosol spray of the topical spray composition.

42. An article of manufacture for treating a dermatophyte skin infection or onychomycosis in a subject in need thereof, the article of manufacture comprising (a) a sealed pressurized container comprising (i) a topical composition according to any one of claims 1 to 37, and (ii) means for providing an aerosol spray of the topical composition, and (b) instructions for use of the topical composition for treating the dermatophyte skin infection or onychomycosis.

43. A method of treating a dermatophyte skin infection or onychomycosis in a subject in need thereof, the method comprising topically administering to the subject a topical composition according to any one of claims 1 to 37.

44. The method of claim 43, wherein the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris.

45. The method of claim 43 or 44, wherein the administering comprises applying the topical composition to the subject in the form of an aerosol spray or mist.

46. ​​The method of any one of claims 43 to 45, wherein the composition is administered no more than once within a three-day period.

47. The method of any one of claims 43 to 46, wherein the composition is administered no more than once over a one-week period.

48. The method of any one of claims 43 to 47, wherein the composition is administered no more than once within a two week period.

49. The method of any one of claims 43 to 48, wherein the topical composition is applied to the subject no more than twice to relieve the dermatophyte skin condition or onychomycosis.

50. The method of any one of claims 43 to 49, wherein the topical composition is applied to the subject once to relieve the dermatophyte skin condition or onychomycosis.

51. The method of any one of claims 43 to 50, wherein the method comprises a first application of the topical composition and a second application of the topical composition.

52. The method of claim 51, wherein the second administration is 5 to 10 days after the first administration.

53. The method of claim 51, wherein the second administration is about 7 days after the first administration.

54. The method of any one of claims 43 to 53, wherein the effectiveness of the treatment of the dermatophyte skin condition is determined by: a. comparing (i) the reduction in clinical scores of subjects treated with the topical composition to (ii) the reduction in clinical scores of subjects treated with placebo or not given treatment; and / or b. Comparing the reduction in percent mycological cure observed in (a) subjects treated with the topical composition with (b) subjects treated with a placebo or given no treatment.

55. The method of any one of claims 43 to 54, wherein systemic levels of naftifine after a single dose of the topical composition average about 100 pg / mL after 4 weeks.

56. A method of treating a dermatophyte skin infection or onychomycosis in a patient, the method comprising administering to the subject one dose or two doses of a topical spray composition comprising naftifine, wherein the topical composition is a single-phase solution and the naftifine is present at at least 80% saturation, wherein if two doses are used, the second dose is administered about 1 week after the first dose.

57. The method of claim 56, wherein the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris.

58. A method for maintaining therapeutic levels of naftifine in the stratum corneum of a subject for at least four weeks, the method comprising administering to the subject one dose or two doses of a topical spray-on composition comprising naftifine, wherein the composition is a single-phase solution and the drug is present at at least 80% of saturation under conditions of use, wherein if two doses are used, the second dose is administered about 1 week after the first dose.

59. A method of treating a dermatophyte skin infection or onychomycosis in a subject in need thereof, the method comprising administering a topical spray composition comprising 2% naftifine or a pharmaceutically acceptable salt thereof, wherein the topical composition is administered to the patient in one dose or in two doses, wherein if two doses are used, the second dose is administered about 1 week after the first dose, wherein said administering said topical composition to said subject achieves at least a 50% success rate of an efficacy endpoint.

60. The method of claim 59, wherein the dermatophyte skin condition is tinea pedis, interdigital tinea pedis, or tinea cruris.

61. The method of claim 59 or claim 60, wherein the efficacy endpoint is achieving complete clearance at day 42 (6 weeks), defined as KOH negative, fungal culture negative, and scores of 0 'none' for individual signs and symptoms including erythema, scaling, and pruritus.

62. A method of treating a dermatophyte skin infection in a subject, the method comprising administering a topical spray composition comprising naftifine, wherein the composition is a single-phase solution and the drug is present at at least 80% of saturation under conditions of use, wherein the administering of the topical composition to the subject achieves complete clearance of clinical signs and symptoms, wherein said complete clearance is characterized by achieving the scores listed in (a) to (c) for said clinical signs and symptoms: (a) On day 42, the severity of erythema decreased relative to baseline, with a score of 0; (b) On day 42, the severity of desquamation decreased relative to baseline, with a score of 0; (c) on day 42, the severity of pruritus decreased relative to baseline, with a score of 0; and characterized by achieving mycological cure in KOH test and mycological culture.

63. A method of treating a dermatophyte skin infection in a subject, the method comprising administering a topical spray composition comprising naftifine, wherein the composition is a single-phase solution and the drug is present at at least 80% of saturation under conditions of use, wherein the administering of the topical composition to the subject achieves complete clearance of clinical signs and symptoms, wherein the complete clearance is characterized by achieving at least one of the scores listed in (a) to (c) for the clinical signs and symptoms: (a) On day 42, the severity of erythema decreased relative to baseline, with a score of 0; (b) On day 42, the severity of desquamation decreased relative to baseline, with a score of 0; (c) on day 42, the severity of pruritus decreased relative to baseline, with a score of 0; and characterized by achieving mycological cure in KOH test and mycological culture.

64. A method of treating a dermatophyte skin infection in a subject, the method comprising administering a topical spray composition comprising naftifine, wherein the composition is a single-phase solution and the drug is present at at least 80% of saturation under conditions of use, wherein the administering of the topical composition to the subject results in a treatment efficacy of at least 20%, wherein the efficacy is negative KOH stain, negative fungal culture, and absent or mild erythema, scaling, and pruritus six weeks after the treatment.

65. The method of claim 64, wherein the method comprises administering a single dose of the topical spray composition.

66. The method of claim 64, wherein the method comprises administering two doses of the topical spray composition.

67. The method of any one of claims 64 to 66, wherein said administering said topical composition to said subject results in a therapeutic efficacy of at least 40%.

68. The method of any one of claims 64 to 66, wherein said administering said topical composition to said subject results in a therapeutic efficacy of at least 70%.

69. The method of any one of claims 62 to 68, wherein the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris.

70. The method of any one of claims 43 to 69, wherein systemic levels of naftifine after a single application of the topical composition average about 100 pg / mL after 4 weeks.

71. A method for maintaining therapeutic levels of naftifine in the stratum corneum of a subject above the minimum inhibitory concentration (MIC) for at least one week, the method comprising administering to the subject a single dose of a topical spray composition comprising naftifine, wherein the composition is a single-phase solution and the drug is present at at least 80% of saturation.

72. A method of treating a dermatophyte skin infection or onychomycosis in a subject in need thereof, the method comprising administering a topical spray composition comprising 2% naftifine or a pharmaceutically acceptable salt thereof, wherein the topical composition is administered to the patient as a single dose, wherein the administering of the topical composition to the subject achieves at least a 50% success rate for an efficacy endpoint.

73. A method for maintaining therapeutic levels of naftifine in the stratum corneum of a subject for at least four weeks, the method comprising administering to the subject a single dose of a topical spray composition comprising naftifine, wherein the composition is a single-phase solution and the drug is present at at least 80% of saturation under conditions of use.

74. A method of treating a dermatophyte skin infection or onychomycosis in a patient, the method comprising administering to the subject a single dose of a topical spray composition comprising naftifine, wherein the topical composition is a single-phase solution and the naftifine is present at at least 80% of saturation.

75. A drug-device combination for dispensing a composition, the drug-device combination comprising: A container comprising a composition comprising: i. naftifine or a pharmaceutically acceptable salt thereof; ii. a film former comprising octyl acrylamide acrylate copolymer; iii. alcohol solvent; and iv. Propellant, wherein the drug-device combination is adapted to provide a spray comprising the composition, wherein the D 90 The droplet size is larger than 1 μm.

76. The drug-device combination of claim 75, wherein when sprayed from the device, the D 90 The droplet size was about 140 μm to about 170 μm.

77. The drug-device combination of claim 75 or 76, wherein when sprayed from the device, the D of the composition is 90 The droplet size is about 150 μm to about 165 μm.

78. The drug-device combination of any one of claims 75 to 77, wherein when sprayed from the device, the average D 90 The droplet size was about 155 μm to 163 μm.

79. The drug-device combination of any one of claims 75 to 78, wherein the naftifine or a pharmaceutically acceptable salt thereof is naftifine hydrochloride.

80. The drug-device combination of any one of claims 75 to 79, wherein the composition comprises about 1% to about 3% of naftifine or a pharmaceutically acceptable salt thereof.

81. The drug-device combination of any one of claims 75 to 80, wherein the composition comprises about 2% naftifine or a pharmaceutically acceptable salt thereof.

82. The drug-device combination of any one of claims 75 to 81, wherein the composition comprises from about 2% w / w to about 10% w / w octylacrylamide acrylate copolymer.

83. The drug-device combination of any one of claims 75 to 82, wherein the composition comprises from about 2% w / w to about 4% w / w octylacrylamide acrylate copolymer.

84. The drug-device combination of any one of claims 75 to 83, wherein the ratio of film former to alcohol solvent in the composition is about 1:15 to 1:30 (w / w).

85. The drug-device combination of any one of claims 75 to 84, wherein the ratio of film former to alcohol solvent in the composition is about 1:18 to 1:22 (w / w).

86. The drug-device combination of any one of claims 75 to 85, wherein the composition comprises less than 4% of a hydrophilic polymer.

87. The drug-device combination of any one of claims 75 to 86, wherein the composition comprises less than 0.5% of a hydrophilic polymer.

88. The drug-device combination of any one of claims 75 to 87, wherein the alcohol solvent is a C1-C6 alcohol.

89. The drug-device combination of claim 88, wherein the C1-C6 alcohol is methanol, ethanol, propanol, n-propanol, isopropanol, n-butanol, tert-butanol, 2-butanol, isobutanol, pentanol, hexanol, cyclohexanol, or a combination thereof.

90. The drug-device combination of claim 89, wherein the C1-C6 alcohol is ethanol.

91. The drug-device combination of any one of claims 75 to 90, wherein the alcohol solvent has a viscosity of about 1 cp to about 150 cp.

92. The drug-device combination of any one of claims 75 to 91, wherein the composition comprises from about 10% to about 70% by weight of an alcohol solvent.

93. The drug-device combination of any one of claims 75 to 92, wherein the composition comprises from about 50% to about 70% by weight of an alcohol solvent.

94. The drug-device combination according to any one of claims 75 to 93, wherein the viscosity of the composition is from about 0.1 cp to about 500 cp.

95. The drug-device combination of any one of claims 75 to 94, wherein the viscosity of the composition is from about 1 cp to about 150 cp.

96. The drug-device combination of any one of claims 75 to 95, wherein the propellant is a hydrocarbon propellant, a fluorocarbon propellant, a hydrofluorocarbon propellant, or a combination thereof.

97. The drug-device combination of any one of claims 75 to 96, wherein the propellant is propane, isobutane, n-butane, isopentane, n-pentane, or a combination thereof.

98. The drug-device combination of any one of claims 75 to 97, wherein the propellant is a hydrofluorocarbon propellant.

99. The drug-device combination of claim 98, wherein the hydrofluorocarbon propellant is 1,1,1,2-tetrafluoroethane (Norflurane 134A) or 1,1-difluoroethane (HFA-152a).

100. The drug-device combination of any one of claims 75 to 99, wherein the composition comprises from about 10% to about 50% by weight of propellant.

101. The drug-device combination of any one of claims 75 to 100, wherein the composition comprises from about 25% to about 45% by weight of propellant.

102. The drug-device combination of any one of claims 75 to 101, wherein the ratio of the alcohol solvent to the propellant is from about 1.5:1 to about 2.5:1 (w / w).

103. The drug-device combination of any one of claims 75 to 102, wherein the ratio of the alcohol solvent to the propellant is about 1:1 to 2:1 (w / w).

104. The drug-device combination of any one of claims 75 to 103, wherein the ratio of the alcohol solvent to the propellant is about 2:1 to 3:1 (w / w).

105. The drug-device combination according to any one of claims 75 to 104, wherein the ratio of film former to propellant is about 1:7 to 1:15 (w / w).

106. The drug-device combination of claim 105, wherein the ratio of film former to propellant is about 1:8 to 1:12 (w / w).

107. The drug-device combination of any one of claims 75 to 106, further comprising a penetration enhancer, a solubilizer, an emulsifier, a solubilizer, or a combination thereof.

108. The drug-device combination of claim 107, wherein the penetration enhancer is a mixture of diethylene glycol monoethyl ether, diethyl sebacate, diisopropyl adipate, dimethyl isosorbide, dimethyl sulfoxide, polyethylene glycol, oleic acid, lactic acid esters, oleyl alcohol, alkyl glycosides, sugar alkyl esters, dimethylformamide, isopropyl myristate, Tween 80, sodium lauryl sulfate, oleic acid, and octyl dimethyl para-aminobenzoic acid, or a combination thereof.

109. The drug-device combination of any one of claims 75 to 108, wherein the pressure inside the device is from about 28 psi to about 145 psi at 25°C.

110. A method of treating a dermatophyte skin infection or onychomycosis in a subject in need thereof, the method comprising applying an aerosol spray or mist to the skin using a device according to any one of claims 75 to 109.

111. The method of claim 110, wherein the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris.

112. The method of claim 111, wherein the composition is administered no more than once within a three-day period.

113. The method of claim 112, wherein the composition is administered no more than once over a one-week period.

114. The method of claim 113, wherein the composition is administered no more than once within a two week period.

115. The method of any one of claims 110 to 114, wherein the composition is administered to the subject no more than twice to alleviate the dermatophyte skin condition or onychomycosis.

116. The method of any one of claims 110 to 115, wherein the composition dries in less than three minutes after applying the composition to the skin.

117. The method of any one of claims 110 to 115, wherein the composition dries in less than two minutes after applying the composition to the skin.

118. The method of any one of claims 110 to 115, wherein the composition dries in less than one minute after applying the composition to the skin.

119. The method of any one of claims 110 to 118, wherein the method comprises a first application of the topical composition and a second application of the composition.

120. The method of claim 119, wherein the second administration is 5 to 10 days after the first administration.

121. The method of claim 120, wherein the second administration is about 7 days after the first administration.

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